1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications

ABSTRACT

Compounds of formula I  
                 
 
     are useful in treating diseases or conditions prevented by or ameliorated with histamine-3 receptor ligands. Also disclosed are histamine-3 receptor ligand compositions and methods of antagonizing or agonizing histamine-3 receptors.

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/902,925 filed Jul. 11, 2001, which claims thebenefit of U.S. Patent Application Serial No. 60/218,084, filed Jul. 13,2000, now abandoned.

TECHNICAL FIELD

[0002] This invention relates to compounds of formula I, which may beuseful for treating diseases or conditions caused by or exacerbated byhistamine-3 receptor activity, pharmaceutical compositions containingcompounds of formula I and methods of treatment using compounds offormula I.

BACKGROUND OF THE INVENTION

[0003] Histamine is a well-known mediator in hypersensitive reactions(e.g. allergies, hay fever, and asthma) which are commonly treated withantagonists of histamine or “antihistamines.” It has also beenestablished that histamine receptors exist in at least two distincttypes, referred to as H₁ and H₂ receptors.

[0004] A third histamine receptor (H₃ receptor) is believed to play arole in neurotransmission in the central nervous system, where the H₃receptor is thought to be disposed presynaptically on histaminergicnerve endings (Nature, 302, 832-837 (1983)). The existence of the H₃receptor has been confirmed by the development of selective H₃ receptoragonists and antagonists (Nature, 327, 117-123 (1987)) and hassubsequently been shown to regulate the release of otherneurotransmitters in both the central nervous system and peripheralorgans, particularly the lungs, cardiovascular system andgastrointestinal tract.

[0005] A number of diseases or conditions may be treated withhistamine-3 receptor ligands wherein the H₃ ligand may be an antagonist,agonist or partially agonist, see: (Imamura et al., Circ.Res., (1996)78, 475-481); (Imamura et. al., Circ.Res., (1996) 78, 863-869); (Lin etal., Brain Res. (1990) 523, 325-330); (Monti et al.,Neuropsychopharmacology (1996) 15, 31-35); (Sakai, et al., Life Sci.(1991) 48, 2397-2404); (Mazurkiewicz-Kwilecki and Nsonwah, Can. J.Physiol. Pharmacol. (1989) 67, 75-78); (Panula, P. et al., Neuroscience(1998) 44, 465-481); (Wada et al., Trends in Neuroscience (1991) 14,415); (Monti et al., Eur. J. Pharmacol. (1991) 205, 283);(Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989)67, 75-78); (Haas et al., Behav. Brain Res. (1995) 66, 41-44); (DeAlmeida and Izquierdo, Arch. Int. Pharmacodyn. (1986) 283, 193-198);(Kamei et al., Psychopharmacology (1990) 102, 312-318); (Kamei andSakata, Jpn. J. Pharmacol. (1991) 57, 437-482); (Schwartz et al.,Psychopharmacology; The fourth Generation of Progress. Bloom and Kupfer(eds). Raven Press, New York, (1995) 397); (Shaywitz et al.,Psychopharmacology (1984) 82,73-77); (Dumery and Blozovski, Exp. BrainRes. (1987) 67, 61-69); (Tedford et al., J. Pharmacol. Exp. Ther. (1995)275, 598-604); (Tedford et al., Soc. Neurosci. Abstr. (1996) 22, 22);(Yokoyama et al., Eur. J. Pharmacol. (1993) 234, 129); (Yokoyama andIinuma, CNS Drugs (1996) 5, 321); (Onodera et al., Prog. Neurobiol.(1994) 42, 685); (Leurs and Timmerman, Prog. Drug Res. (1992) 39, 127);(The Histamine H₃ Receptor, Leurs and Timmerman (eds), Elsevier Science,Amsterdam, The Netherlands (1998); (Leurs et al., Trends in Pharm. Sci.(1998) 19, 177-183); (Phillips et al., Annual Reports in MedicinalChemistry (1998) 33, 31-40); (Matsubara et al., Eur. J. Pharmacol.(1992) 224, 145); (Rouleau et al., J. Pharmacol. Exp. Ther. (1997) 281,1085); (Adam Szelag, “Role of histamine H₃-receptors in theproliferation of neoplastic cells in vitro”, Med. Sci. Monit., 4(5):747-755, (1998)); (Fitzsimons, C., H. Duran, F. Labombarda, B. Molinariand E. Rivera, “Histamine receptors signalling in epidermal tumor celllines with H-ras gene alterations”, Inflammation Res., 47 (Suppl 1):S50-S51, (1998)); (R. Leurs, R. C. Vollinga and H. Timmerman, “Themedicinal chemistry and therapeutic potentials of ligand of thehistamine H₃ receptor”, Progress in Drug Research 45: 170-165, (1995));(R. Levi and N. C. E. Smith, “Histamine H₃-receptors: A new frontier inmyocardial ischemia”, J. Pharm. Exp. Ther., 292: 825-830, (2000));(Hatta, E., K Yasuda and R. Levi, “Activation of histamine H₃ receptorsinhibits carrier-mediated norepinephrine release in a human model ofprotracted myocradial ischemia”, J. Pharm. Exp. Ther., 283: 494-500,(1997); (H. Yokoyama and K. Iinuma, “Histamine and Seizures:Implications for the treatment of epilepsy”, CNS Drugs, 5(5); 321-330,(1995)); (K. Hurukami, H. Yokoyama, K. Onodera, K. Iinuma and T.Watanabe, AQ-0145, “A newly developed histamine H₃ antagonist, decreasedseizure susceptibility of eletrically induced convulsions in mice”,Meth. Find. Exp. Clin. Pharmacol., 17(C): 70-73, (1995); (Delaunois A.,Gustin P., Garbarg M., and Ansay M., “Modulation of acetylcholine,capsaicin and substance P effects by histamine H₃ receptors in isolatedperfused rabbit lungs”, European Journal of Pharmacology277(2-3):243-50, (1995)); and (Dimitriadou, et al., “Functionalrelationship between mast cells and C-sensitive nerve fibres evidencedby histamine H₃-receptor modulation in rat lung and spleen”, ClinicalScience. 87(2):151-63, (1994). Such diseases or conditions includecardiovascular disorders such as acute myocardial infarction; memoryprocesses, dementia and cognition disorders such as Alzheimer's diseaseand attention-deficit hyperactivity disorder; neurological disorderssuch as Parkinson's disease, schizophrenia, depression, epilepsy, andseizures or convulsions; cancer such as cutaneous carcinoma, medullarythyroid carcinoma and melanoma; respiratory disorders such as asthma;sleep disorders such as narcolepsy; vestibular dysfunction such asMeniere's disease; gastrointestinal disorders, inflammation, migraine,motion sickness, obesity, pain, and septic shock.

[0006] WO 00/06254 describes non-imidazole alkylamines as histamine-3receptor ligands. EP 0 978 512 A1 describes non-imidazole aryloxyalkylamines as histamine-3 receptor ligands.

SUMMARY OF THE INVENTION

[0007] In its principle embodiment, the present invention disclosescompounds of formula I:

[0008] or a pharmaceutically acceptable salt thereof, wherein

[0009] Z is selected from a covalent bond or CH₂;

[0010] R₁ is selected from OR₂, NR₃R₄ or

[0011] R₂ is selected from hydrogen, alkoxycarbonyl, alkyl,alkylcarbonyl, aminocarbonyl, sulfono or phosphono;

[0012] R₃ and R₄ are independently selected from hydrogen, alkenyl,alkenylcarbonyl, alkenyloxycarbonyl, alkenylsulfonyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkynylcarbonyl,alkynyloxycarbonyl, alkynylsulfonyl, aminocarbonyl, aminosulfonyl,arylalkyl, arylalkenylcarbonyl, arylalkenylsulfonyl, arylalkylcarbonyl,arylalkylsulfonyl, arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl,arylheterocylecarbonyl, arylheterocylesulfonyl, aryloxyarylcarbonyl,aryloxyarylsulfonyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkylcarbonyl, cycloalkylalkylsulfonyl, cycloalkylcarbonyl,cycloalkylsulfonyl, formyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclealkylsulfonyl,heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl,heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl,heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl,heterocycleoxyarylsulfonyl, heterocyclesulfonyl, orheterocyclethioalkylcarbonyl;

[0013] R₅ and R₆ are independently selected from hydrogen or alkyl;

[0014] R₇ is selected from hydrogen or alkyl; or

[0015] R₁ and R₇ together form (═O);

[0016] R₈ is selected from alkylcarbonyl, aryl, arylcarbonyl,arylcarbonylaryl, arylcarbonylheterocycle, cycloalkylcarbonyl,cycloalkylcarbonylaryl, cycloalkylcarbonylheterocycle, heterocycle,heterocyclecarbonyl, heterocyclecarbonylaryl orheterocyclecarbonylheterocycle;

[0017] R₉ is selected from the hydrogen or lower alkyl; and

[0018] R_(A), R_(B), R_(C) and R_(D) are independently selected fromhydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl,alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, carboxy,carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, mercapto or nitro.

DETAILED DESCRIPTION OF THE INVENTION

[0019] All patents, patent applications, and literature references citedin the specification are herein incorporated by reference in theirentirety.

[0020] It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

[0021] In its principle embodiment, the present invention disclosescompounds of formula I:

[0022] or a pharmaceutically acceptable salt, ester, amide or prodrugthereof, wherein

[0023] Z is selected from a covalent bond or CH₂;

[0024] R₁ is selected from OR₂, NR₃R₄ or

[0025] R₂ is selected from hydrogen, alkoxycarbonyl, alkyl,alkylcarbonyl, aminocarbonyl, sulfono and phosphono; R₃ and R₄ areindependently selected from hydrogen, alkenyl, alkenylcarbonyl,alkenyloxycarbonyl, alkenylsulfonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, alkynyl, alkynylcarbonyl,alkynyloxycarbonyl, alkynylsulfonyl, aminocarbonyl, aminosulfonyl,arylalkyl, arylalkenylcarbonyl, arylalkenylsulfonyl, arylalkylcarbonyl,arylalkylsulfonyl, arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl,arylheterocylecarbonyl, arylheterocylesulfonyl, aryloxyarylcarbonyl,aryloxyarylsulfonyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkylcarbonyl, cycloalkylalkylsulfonyl, cycloalkylcarbonyl,cycloalkylsulfonyl, formyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclealkylsulfonyl,heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl,heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl,heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl,heterocycleoxyarylsulfonyl, heterocyclesulfonyl orheterocyclethioalkylcarbonyl;

[0026] R₅ and R₆ are independently selected from hydrogen or alkyl;

[0027] R₇ is selected from hydrogen or alkyl; or

[0028] R₁ and R₇ together form (═O);

[0029] R₈ is selected from alkylcarbonyl, aryl, arylcarbonyl,arylcarbonylaryl, arylcarbonylheterocycle, cycloalkylcarbonyl,cycloalkylcarbonylaryl, cycloalkylcarbonylheterocycle, heterocycle,heterocyclecarbonyl, heterocyclecarbonylaryl orheterocyclecarbonylheterocycle;

[0030] R₉ is selected from hydrogen or lower alkyl; and

[0031] R_(A), R_(B), R_(C) and R_(D) are independently selected fromhydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl,alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, carboxy,carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, mercapto or nitro;

[0032] wherein at each occurrence of said aryl, arylalkenylcarbonyl,arylalkenylsulfonyl, arylalkylcarbonyl, arylalkylsulfonyl,arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl, arylcarbonylaryl,arylcarbonylheterocycle, arylheterocylecarbonyl, arylheterocylesulfonyl,aryloxyarylcarbonyl, aryloxyarylsulfonyl, arylsulfonyl,cycloalkylcarbonylaryl, heterocyclearylcarbonyl,heterocyclearylsulfonyl, heterocyclecarbonylaryl,heterocycleoxyarylcarbonyl, and heterocycleoxyarylsulfonyl, the arylportion can be optionally substituted with 1, 2, or 3 substituentsselected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl,alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy,haloalkyl, hydroxy, hydroxyalkyl, mercapto or nitro; and

[0033] wherein at each occurrence of said arylcarbonylheterocycle,arylheterocylecarbonyl, arylheterocylesulfonyl,cycloalkylcarbonylheterocycle, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclealkylsulfonyl,heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl,heterocyclecarbonylaryl, heterocyclecarbonylheterocycle,heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl,heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl,heterocycleoxyarylsulfonyl, heterocyclesulfonyl, andheterocyclethioalkylcarbonyl, the heterocycle portion can be optionallysubstituted with 1, 2, or 3 substituents selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl,amino, aminoalkyl, aminocarbonyl, aminosulfonyl, carboxy, carboxyalkyl,cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, mercapto or nitro.

[0034] In a preferred embodiment, compounds of the present inventionhave formula I wherein R₁ is NR₃R₄; R₃ and R₄ are independently selectedfrom hydrogen, alkenyl, alkenylcarbonyl, alkenyloxycarbonyl,alkenylsulfonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl,alkynyl, alkynylcarbonyl, alkynyloxycarbonyl, alkynylsulfonyl,aminocarbonyl, aminosulfonyl, arylalkyl, arylalkenylcarbonyl,arylalkenylsulfonyl, arylalkylcarbonyl, arylalkylsulfonyl,arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl,arylheterocylecarbonyl, arylheterocylesulfonyl, aryloxyarylcarbonyl,aryloxyarylsulfonyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkylcarbonyl, cycloalkylalkylsulfonyl, cycloalkylcarbonyl,cycloalkylsulfonyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclealkylsulfonyl,heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl,heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl,heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl,heterocycleoxyarylsulfonyl, heterocyclesulfonyl orheterocyclethioalkylcarbonyl; R₇ is hydrogen; R₈ is selected fromalkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle,heterocyclecarbonylaryl or heterocyclecarbonylheterocycle; and Z, R₉,R_(A), R_(B), R_(C) and R_(D) are as defined in formula I.

[0035] In another preferred embodiment, compounds of the presentinvention have formula I wherein R₁ is NR₃R₄; R₃ and R₄ areindependently selected from hydrogen, alkenyloxycarbonyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aminocarbonyl,aminosulfonyl, arylalkenylsulfonyl, arylcarbonyl, arylsulfonyl,cycloalkylcarbonyl, heterocyclecarbonyl, heterocycleheterocyclecarbonyl,heterocycleheterocyclesulfonyl, heterocycleoxyarylsulfonyl,heterocyclesulfonyl, and heterocyclethioalkylcarbonyl; R₇ is hydrogen;R₈ is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl,heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle;and Z, R₉, R_(A), R_(B), R_(C) and R_(D) are as defined in formula I.

[0036] In another preferred embodiment, compounds of the presentinvention have formula I wherein Z is CH₂; R₁ is NR₃R₄; R₃ and R₄ areindependently selected from hydrogen, alkoxycarbonyl or alkyl; R₇ ishydrogen; R₈ is selected from acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen.

[0037] In another preferred embodiment, compounds of the presentinvention have formula I wherein Z is a covalent bond; R₁ is NR₃R₄; R₃and R₄ are independently selected from hydrogen, alkoxycarbonyl oralkyl; R₇ is hydrogen; R₈ is selected from acetyl, propionyl,cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl;R₉ is hydrogen; and R_(A), R_(B), R_(C) and R_(D) are independentlyselected from hydrogen or halogen.

[0038] In another preferred embodiment, compounds of the presentinvention have formula II

[0039] or a pharmaceutically acceptable salt, ester, amide or prodrugthereof wherein RIO is selected from alkenyl, alkyl, alkynyl, amino,aryl, arylalkenyl, arylalkyl, arylaryl, arylheterocycle, aryloxyaryl,cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl,heterocyclearyl, heterocycleheterocycle or heterocycleoxyaryl; and Z,R₃, R₈, R₉ R_(A), R_(B), R_(C) and R_(D) are as defined in formula I.

[0040] In another preferred embodiment, compounds of the presentinvention have formula II wherein R₃ is selected from hydrogen or alkyl;R₈ is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl,heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle;R₁₀ is selected from alkyl, amino, aryl, arylalkenyl, heterocycle,heterocycleheterocycle or heterocycleoxyaryl; and Z, R₉, R_(A), R_(B),R_(C) and R_(D) are as defined in formula I.

[0041] In another preferred embodiment, compounds of the presentinvention have formula II wherein Z is CH₂; R₃ is selected from hydrogenor alkyl; R₈ is selected from acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₀ is selected from alkyl or amino.

[0042] In another preferred embodiment, compounds of the presentinvention have formula II wherein Z is CH₂; R₃ is selected from hydrogenor alkyl; R₈ is selected from acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₀ is aryl wherein said aryl is phenyl optionallysubstituted with 1 or 2 substitutuents selected from alkoxy, alkyl,alkylsufonyl, amino, cyano, haloalkoxy, haloalkyl or halogen.

[0043] In another preferred embodiment, compounds of the presentinvention have formula II wherein Z is CH₂; R₃ is selected from hydrogenor alkyl; R₈ is selected from acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1 -piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₀ is arylalkenyl wherein the aryl portion of saidarylalkenyl is phenyl.

[0044] In another preferred embodiment, compounds of the presentinvention have formula II wherein Z is CH₂; R₃ is selected from hydrogenor alkyl; R₈ is selected from acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1 -piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₀ is heterocycle wherein said heterocycle is selectedfrom benzothienyl, imidazolyl, isoquinolinyl, pyridinyl, pyrrolyl,quinolinyl, thiazolyl or thienyl, wherein said benzothienyl, imidazolyl,isoquinolinyl, pyridinyl, pyrrolyl, quinolinyl, thiazolyl or thienyl isoptionally substituted with 1 or 2 substitutuents selected from alkoxy,alkyl, amino, haloalkyl or halogen.

[0045] In another preferred embodiment, compounds of the presentinvention have formula II wherein Z is CH₂; R₃ is selected from hydrogenor alkyl; R₈ is selected from acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₈ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhydrogen; and R₁₀ is heterocycleheterocycle wherein saidheterocycleheterocycle is(3-chloro-5-(trifluoromethyl)-2-pyridinyl)-1H-pyrrol-2-yl.

[0046] In another preferred embodiment, compounds of the presentinvention have formula II wherein Z is CH₂; R₃ is selected from hydrogenor alkyl; R₈ is selected from acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are indepoendently selected from hydrogen orhalogen; and R₁₀ is heterocycleoxyaryl wherein said heterocycleoxyarylis (3-chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenyl).

[0047] In another preferred embodiment, compounds of the presentinvention have formula III

[0048] or a pharmaceutically acceptable salt, ester, amide or prodrugthereof wherein R₁₁ is selected from hydrogen, alkenyl, alkenyloxy,alkoxy, alkyl, alkynyl, alkynyloxy, amino, aryl, arylalkenyl, arylalkyl,arylaryl, arylheterocycle, aryloxyaryl, cycloalkyl, cycloalkylalkyl,heterocycle, heterocyclealkyl, heterocyclearyl, heterocycleheterocycle,heterocycleoxyalkyl, heterocycleoxyaryl or heterocyclethioalkyl; and Z,R₃, R₈, R₉, R_(A), R_(B), R_(C) and R_(D) are as defined in formula I.

[0049] In another preferred embodiment, compounds of the presentinvention have formula III wherein R₃ is selected from hydrogen, alkyl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, and heterocyclecarbonyl; R₈is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle,heterocyclecarbonylaryl and heterocyclecarbonylheterocycle; and R₁₁ isselected from alkenyloxy, alkoxy, alkyl, amino, aryl, cycloalkyl,heterocycle, heterocycleheterocycle or heterocyclethioalkyl; and Z, R₉,R_(A), R_(B), R_(C) and R_(D) are as defined in formula I.

[0050] In another preferred embodiment, compounds of the presentinvention have formula III wherein Z is CH₂; R₃ is selected fromhydrogen, alkyl, alkylcarbonyl, and aminocarbonyl; R₈ is selected fromacetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl,4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl,2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₁ is selected from alkenyloxy, alkoxy, alkyl, amino orcycloalkyl.

[0051] In another preferred embodiment, compounds of the presentinvention have formula III wherein Z is CH₂; R₃ is selected fromhydrogen, alkyl or arylcarbonyl wherein the aryl portion of saidarylcarbonyl is phenyl optionally substituted with 1 substituentselected from cyano or halogen; R₈ is selected from acetyl, propionyl,cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₁ is aryl wherein said aryl is phenyl optionallysubstituted with 1 substituent selected from cyano or halogen.

[0052] In another preferred embodiment, compounds of the presentinvention have formula III wherein Z is CH₂; R₃ is selected fromhydrogen, alkyl or heterocyclecarbonyl wherein the heterocycle portionof said heterocyclecarbonyl is selected from 4-morpholinyl or1-pyrrolidinyl; R₈ is selected from acetyl, propionyl,cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₁ is heterocycle wherein said heterocycle is selectedfrom furyl, 4-morpholinyl, pyridinyl or pyrrolidinyl.

[0053] In another preferred embodiment, compounds of the presentinvention have formula III wherein Z is CH₂; R₃ is selected fromhydrogen or alkyl; R₈ is selected from acetyl, propionyl,cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₁ is heterocycleheterocycle wherein saidheterocycleheterocycle is 2-(3-pyridinyl)-1,3-thiazol-4-yl.

[0054] In another preferred embodiment, compounds of the presentinvention have formula III wherein Z is CH₂; R₃ is selected fromhydrogen or alkyl; R₈ is selected from acetyl, propionyl,cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₁₁ is heterocyclethioalkyl wherein saidheterocyclethioalkyl is [(4-methyl-2-pyrimidinyl)sulfanyl]methyl.

[0055] In another preferred embodiment, compounds of the presentinvention have formula IV

[0056] or a pharmaceutically acceptable salt, ester, amide or prodrugthereof wherein R₃ and R4 are independently selected from hydrogen,alkenyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocycle or heterocyclealkyl; and Z, R₈, R₉, R_(A), R_(B), R_(C) andR_(D) are as defined in formula I.

[0057] In another preferred embodiment, compounds of the presentinvention have formula IV wherein R₃ and R₄ are independently selectedfrom hydrogen or alkyl; R₈ is selected from alkylcarbonyl,cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl orheterocyclecarbonylheterocycle; and Z, R₉, R_(A), R_(B), R_(C) and R_(D)are as defined in formula I.

[0058] In another preferred embodiment, compounds of the presentinvention have formula IV wherein Z is CH₂; R₃ and R₄ are independentlyalkyl; R₈ is selected from acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen, alkoxy,alkyl or halogen.

[0059] In another preferred embodiment, compounds of the presentinvention have formula IV wherein Z is CH₂; R₃ and R₄ are independentlyselected from hydrogen or alkyl; R₈ is selected from acetyl, propionyl,cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; and R₉ is hydrogen; andR_(A), R_(B), R_(C) and R_(D) are independently selected from hydrogenor halogen.

[0060] In another preferred embodiment, compounds of the presentinvention have formula IV wherein Z is CH₂; R₃ and R₄ are independentlyalkyl; R₉ is 4-cyanophenyl; R₉, R_(B), R_(C) and R_(D) are hydrogen; andR_(A) is selected from alkoxy, alkyl or halogen.

[0061] In another preferred embodiment, compounds of the presentinvention have formula IV wherein Z is CH₂; R₃ and R₄ are independentlyalkyl; R8 is 4-cyanophenyl; R₉, R_(A), R_(C) and R_(D) are hydrogen; andR_(B) is alkyl.

[0062] In another preferred embodiment, compounds of the presentinvention have formula IV wherein Z is CH₂; R₃ and R₄ are independentlyalkyl; R₉ is 4-cyanophenyl; R₉, R_(B) and R_(C) are hydrogen; and R_(A)and R_(D) are independently halogen.

[0063] In another preferred embodiment, compounds of the presentinvention have formula V

[0064] or a pharmaceutically acceptable salt, ester, amide or prodrugthereof wherein Z, R₂, R₇, R₈, R₉, R_(A), R_(B), R_(C) and R_(D) are asdefined in formula I.

[0065] In another preferred embodiment, compounds of the presentinvention have formula V wherein R₈ is selected from alkylcarbonyl,cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl orheterocyclecarbonylheterocycle; and Z, R₂, R₇, R₉, R_(A), R_(B), R_(C)and R_(D) are as defined in formula I.

[0066] In another preferred embodiment, compounds of the presentinvention have formula V wherein Z is CH₂; R₈ is selected from acetyl,propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₂ and R₇ are as defined in formula I.

[0067] In another preferred embodiment, compounds of the presentinvention have formula VI

[0068] or a pharmaceutically acceptable salt, ester, amide or prodrugthereof wherein Z, R₈, R₉, R_(A), R_(B), R_(C) and R_(D) are as definedin formula I.

[0069] In another preferred embodiment, compounds of the presentinvention have formula VI wherein R₈ is selected from alkylcarbonyl,cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl orheterocyclecarbonylheterocycle; Z, R₉, R_(A), R_(B), R_(C) and R_(D) areas defined in formula I.

[0070] In another preferred embodiment, compounds of the presentinvention have formula VI wherein Z is CH₂; R₈ is selected from acetyl,propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen.

[0071] In another preferred embodiment, compounds of the presentinvention have formula VII

[0072] or a pharmaceutically acceptable salt, ester, amide or prodrugthereof wherein Z, R₅, R₆, R₈, R₉, R_(A), R_(B), R_(C) and R_(D) are asdefined in formula I.

[0073] In another preferred embodiment, compounds of the presentinvention have formula VII wherein R₈ is selected from alkylcarbonyl,cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl orheterocyclecarbonylheterocycle; Z, R₅, R₆, R₉, R_(A), R_(B), R_(C) andR_(D) are as defined in formula I.

[0074] In another preferred embodiment, compounds of the presentinvention have formula VII wherein Z is CH₂; R₈ is selected from acetyl,propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenylor 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from hydrogen orhalogen; and R₅ and R₆ are as defined in formula I.

[0075] Another embodiment of the present invention relates topharmaceutical compositions comprising a therapeutically effectiveamount of a compound of formula I-VII or a pharmaceutically acceptablesalt, ester, amide, or prodrug thereof in combination with apharmaceutically acceptable carrier.

[0076] Another embodiment of the invention relates to a method ofmodulating the effects of the histamine-3 receptor by agonism of thehistamine-3 receptor in a mammal comprising administering atherapeutically effective amount of a compound of formula I-VII or apharmaceutically acceptable salt, ester, amide, or prodrug thereof incombination with a pharmaceutically acceptable carrier.

[0077] Another embodiment of the invention relates to a method ofmodulating the effects of the histamine-3 receptor by antagonism of thehistamine-3 receptor in a mammal comprising administering atherapeutically effective amount of a compound of formula I-VII or apharmaceutically acceptable salt, ester, amide, or prodrug thereof incombination with a pharmaceutically acceptable carrier.

[0078] Another embodiment of the invention relates to a method oftreating acute myocardial infarction, asthma, bipolar disorder,cognitive enhancement, cognitive deficits in psychiatric disorders,cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders,inflammation, jet lag, medullary thyroid carcinoma, melanoma, Meniere'sdisease, migraine, mood and attention alteration, motion sickness,neurogenic inflammation, obsessive compulsive disorder, pain,Parkinson's disease, schizophrenia, seizures, septic shock, Tourette'ssyndrome, vertigo, or wakefulness comprising administering atherapeutically effective amount of a compound of formula I-VII or apharmaceutically acceptable salt, ester, amide, or prodrug thereof incombination with a pharmaceutically acceptable carrier.

[0079] Another embodiment of the invention relates to a method oftreating mild cognitive impairment, deficits of memory, deficits oflearning and dementia comprising administering a therapeuticallyeffective amount of a compound of formula I-VII or a pharmaceuticallyacceptable salt, ester, amide, or prodrug thereof in combination with apharmaceutically acceptable carrier.

[0080] Definition of Terms

[0081] As used throughout this specification and the appended claims,the following terms have the following meanings:

[0082] The term “alkenyl,” as used herein, refers to a straight orbranched chain hydrocarbon containing from 2 to 10 carbons andcontaining at least one carbon-carbon double bond formed by the removalof two hydrogens. Representative examples of alkenyl include, but arenot limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

[0083] The term “alkenylcarbonyl,” as used herein, refers to an alkenylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofalkenylcarbonyl include, but are not limited to, 3-butenoyl,3-pentenoyl, and 4-pentenoyl.

[0084] The term “alkenyloxy,” as used herein, refers to an alkenylgroup, as defined herein, appended to the parent molecular moietythrough an oxy group, as defined herein. Representative examples ofalkenyloxy include, but are not limited to, allyloxy, 2-butenyloxy, and3-butenyloxy.

[0085] The term “alkenyloxycarbonyl,” as used herein, refers to analkenyloxy group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of alkenyloxycarbonyl include, but are not limited to,allyloxycarbonyl, 2-butenyloxycarbonyl, and 3-butenyloxycarbonyl.

[0086] The term “alkenylsulfonyl,” as used herein, refers to an alkenylgroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples ofalkenylsulfonyl include, but are not limited to, allylsulfonyl,2butenylsulfonyl, and 3-butenylsulfonyl.

[0087] The term “alkoxy,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through an oxymoiety, as defined herein. Representative examples of alkoxy include,but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, and hexyloxy.

[0088] The term “alkoxyalkoxy,” as used herein, refers to an alkoxygroup, as defined herein, appended to the parent molecular moietythrough another alkoxy group, as defined herein. Representative examplesof alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy,2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.

[0089] The term “alkoxyalkyl,” as used herein, refers to an alkoxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxyalkyl include, but are not limited to, tert-butoxymethyl,2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

[0090] The term “alkoxycarbonyl,” as used herein, refers to an alkoxygroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

[0091] The term “alkyl,” as used herein, refers to a straight orbranched chain hydrocarbon containing from 1 to 10 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

[0092] The term “alkylcarbonyl,” as used herein, refers to an alkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

[0093] The term “alkylcarbonyloxy,” as used herein, refers to analkylcarbonyl group, as defined herein, appended to the parent molecularmoiety through an oxy moiety, as defined herein. Representative examplesof alkylcarbonyloxy include, but are not limited to, acetyloxy,ethylcarbonyloxy, and tert-butylcarbonyloxy.

[0094] The term “alkylsulfinyl,” as used herein, refers to an alkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfinyl group, as defined herein. Representative examples ofalkylsulfinyl include, but are not limited to, methylsulfinyl andethylsulfinyl.

[0095] The term “alkylsulfonyl,” as used herein, refers to an alkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, ethylsulfonyl,isopropylsulfonyl, and methylsulfonyl.

[0096] The term “alkylthio,” as used herein, refers to an alkyl group,as defined herein, appended to the parent molecular moiety through athio moiety, as defined herein. Representative examples of alkylthioinclude, but are not limited to, methylsulfanyl, ethylsulfanyl,tert-butylsulfanyl, and hexylsulfanyl.

[0097] The term “alkynyl,” as used herein, refers to a straight orbranched chain hydrocarbon group containing from 2 to 10 carbon atomsand containing at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited to, acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0098] The term “alkynylcarbonyl,” as used herein, refers to an alkynylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofalkynylcarbonyl include, but are not limited to, 3-butynoyl,3-pentynoyl, and 4-pentynoyl.

[0099] The term “alkynyloxy,” as used herein, refers to an alkynylgroup, as defined herein, appended to the parent molecular moietythrough an oxy group, as defined herein. Representative examples ofalkynyloxy include, but are not limited to, 2-butynyloxy, and3-butynyloxy.

[0100] The term “alkynyloxycarbonyl,” as used herein, refers to analkynyloxy group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of alkynyloxycarbonyl include, but are not limited to,2-butynyloxycarbonyl, and 3-butynyloxycarbonyl.

[0101] The term “alkynylsulfonyl,” as used herein, refers to an alkynylgroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples ofalkynylsulfonyl include, but are not limited to, 2-butynylsulfonyl, and3-butynylsulfonyl.

[0102] The term “amino,” as used herein, refers to a —NR_(A)R_(B) groupwherein R_(A) and R_(B) are independently selected from hydrogen, alkyl,alkylcarbonyl, and benzyl. Representative examples of amino include butare not limited to acetylamino, amino, benzylamino, dimethylamino, andmethylamino.

[0103] The term “aminoalkyl,” as used herein, refers to an amino group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of aminoalkylinclude, but are not limited, (amino)methyl, (dimethylamino)methyl,2-(benzylamino)ethyl, and (ethylamino)methyl.

[0104] The term “aminocarbonyl,” as used herein, refers to an aminogroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofaminocarbonyl include, but are not limited, aminocarbonyl,dimethylaminocarbonyl, benzylaminocarbonyl, and ethylaminocarbonyl.

[0105] The term “aminosulfonyl,” as used herein, refers to an aminogroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples ofaminosulfonyl include, but are not limited, aminosulfonyl,dimethylaminosulfonyl, benzylaminosulfonyl, and ethylaminosulfonyl.

[0106] The term “aryl,” as used herein, refers to a monocyclic-ringsystem, or a bicyclic- or a tricyclic-fused ring system wherein one ormore of the fused rings are aromatic. Representative examples of arylinclude, but are not limited to, anthracenyl, azulenyl, fluorenyl,indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

[0107] The aryl groups of this invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl,amino, aminoalkyl, aminocarbonyl, aminosulfonyl, carboxy, carboxyalkyl,cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, mercapto, and nitro.

[0108] The term “arylalkenyl,” as used herein, refers to an aryl group,as defined herein, appended to the parent molecular moiety through analkenyl group, as defined herein. Representative examples of arylalkenylinclude, but are not limited to, 3-phenyl-1-propenyl, and2-(2-naphthyl)ethenyl.

[0109] The term “arylalkenylcarbonyl,” as used herein, refers to anarylalkenyl group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of arylalkenylcarbonyl include, but are not limited to,4-phenyl-3-butenoyl, and 3-phenyl-2-propenoyl.

[0110] The term “arylalkenylsulfonyl,” as used herein, refers to anarylalkenyl group, as defined herein, appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples of arylalkenylsulfonyl include, but are not limited to,2-phenylethenylsulfonyl, and 4-phenyl-3-butenylsulfonyl.

[0111] The term “arylalkyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

[0112] Representative examples of arylalkyl include, but are not limitedto, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

[0113] The term “arylalkylcarbonyl,” as used herein, refers to anarylalkyl group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of arylalkylcarbonyl include, but are not limited to,phenylacetyl, 4-phenylbutanoyl, and 3-phenylpropanoyl.

[0114] The term “arylalkylsulfonyl,” as used herein, refers to anarylalkyl group, as defined herein, appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples of arylalkylsulfonyl include, but are not limited to,(2-phenylethyl)sulfonyl, and (3-phenylpropyl)sulfonyl.

[0115] The term “arylaryl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through anotheraryl group, as defined herein. Representative examples of arylarylinclude, but are not limited to, (1,1′-biphenyl), and(2′-chloro(1,1′-biphenyl)-3-yl).

[0116] The term “arylarylcarbonyl,” as used herein, refers to anarylaryl group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of arylarylcarbonyl include, but are not limited to,(1,1′-biphenyl)carbonyl, and (2′-chloro(1,1′-biphenyl)-3-yl)carbonyl.

[0117] The term “arylarylsulfonyl,” as used herein, refers to anarylaryl group, as defined herein, appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples of arylarylsulfonyl include, but are not limited to,(1,1′-biphenyl)sulfonyl, and (2′-chloro(1,1 ′-biphenyl)-3-yl)sulfonyl.

[0118] The term “arylcarbonyl,” as used herein, refers to an aryl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofarylcarbonyl include, but are not limited to, benzoyl, 4-cyanobenzoyl,and naphthoyl.

[0119] The term “arylcarbonylaryl,” as used herein, refers to anarylcarbonyl group, as defined herein, appended to the parent molecularmoiety through an aryl group, as defined herein. Representative examplesof arylcarbonylaryl include, but are not limited to, 4-(benzoyl)phenyland 4-(benzoyl)naphthyl.

[0120] The term “arylcarbonylheterocycle,” as used herein, refers to anarylcarbonyl group, as defined herein, appended to the parent molecularmoiety through a heterocycle group, as defined herein. Representativeexamples of arylcarbonylheterocycle include, but are not limited to,4-benzoyl-1-piperazinyl and 1-benzoyl-4-piperidinyl.

[0121] The term “arylheterocycle,” as used herein, refers to an arylgroup, as defined herein, appended to the parent molecular moietythrough a heterocycle group, as defined herein. Representative examplesof arylheterocycle include, but are not limited to, 5-phenylpyridin-2-yland 5-(3-chlororphenyl)pyridin-2-yl.

[0122] The term “arylheterocyclecarbonyl,” as used herein, refers to anarylheterocycle group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of arylheterocyclecarbonyl include, but are notlimited to, 5-phenylpyridin-2-ylcarbonyl and5-(3-chlororphenyl)pyridin-2-ylcarbonyl.

[0123] The term “arylheterocyclesulfonyl,” as used herein, refers to anarylheterocycle group, as defined herein, appended to the parentmolecular moiety through a sulfonyl group, as defined herein.Representative examples of arylheterocyclesulfonyl include, but are notlimited to, 5-phenylpyridin-2-ylsulfonyl and5-(3-chlororphenyl)pyridin-2-ylsulfonyl.

[0124] The term “aryloxy,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through an oxymoiety, as defined herein. Representative examples of aryloxy include,but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy,4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy.

[0125] The term “aryloxyaryl,” as used herein, refers to an aryloxygroup, as defined herein, appended to the parent molecular moietythrough an aryl group, as defined herein.

[0126] Representative examples of aryloxyaryl include, but are notlimited to, 3-(3-methylphenoxy)phenyl, and 3-(3-bromophenoxy)phenyl.

[0127] The term “aryloxyarylcarbonyl,” as used herein, refers to anaryloxyaryl group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of aryloxyarylcarbonyl include, but are not limited to,3-(3-methylphenoxy)benzoyl, and 3-(3-bromophenoxy)benzoyl.

[0128] The term “aryloxyarylsulfonyl,” as used herein, refers to anaryloxyaryl group, as defined herein, appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples of aryloxyarylsulfonyl include, but are not limited to,3-(3-methylphenoxy)phenylsulfonyl, and 3-(3-bromophenoxy)phenylsulfonyl.

[0129] The term “arylsulfonyl,” as used herein, refers to an aryl group,as defined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein.

[0130] Representative examples of arylsulfonyl include, but are notlimited to, phenylsulfonyl, (4-acetylaminophenyl)sulfonyl,(4-chlorophenyl)sulfonyl, (4-cyanophenyl)sulfonyl,(4-methoxyphenyl)sulfonyl, (4-methylphenyl)sulfonyl, and(4-(tert-butyl)phenyl)sulfonyl.

[0131] The term “arylthio,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through a thiomoiety, as defined herein.

[0132] Representative examples of arylthio include, but are not limitedto, phenylsulfanyl, naphth-2-ylsulfanyl, and 5-phenylhexylsulfanyl.

[0133] The term “carbonyl,” as used herein, refers to a —C(O)— group.

[0134] The term “carboxy,” as used herein, refers to a —CO₂H group.

[0135] The term “carboxyalkyl,” as used herein, refers to a carboxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofcarboxyalkyl include, but are not limited to, carboxymethyl,2-carboxyethyl, and 3-carboxypropyl.

[0136] The term “cyano,” as used herein, refers to a —CN group.

[0137] The term “cyanoalkyl,” as used herein, refers to a cyano group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of cyanoalkylinclude, but are not limited to, cyanomethyl, 2-cyanoethyl, and3-cyanopropyl.

[0138] The term “cycloalkyl,” as used herein, refers to a saturatedcyclic hydrocarbon group containing from 3 to 8 carbons. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl.

[0139] The term “cycloalkylalkyl,” as used herein, refers to cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofcycloalkylalkyl include, but are not limited to, cyclopropylmethyl,2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and4-cycloheptylbutyl.

[0140] The term “cycloalkylalkylcarbonyl,” as used herein, refers tocycloalkylalkyl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of cycloalkylalkylcarbonyl include, but are notlimited to, cyclopropylmethylcarbonyl, 2-cyclobutylethylcarbonyl,cyclopentylmethylcarbonyl, cyclohexylmethylcarbonyl, and4-cycloheptylbutylcarbonyl.

[0141] The term “cycloalkylalkylsulfonyl,” as used herein, refers tocycloalkylalkyl group, as defined herein, appended to the parentmolecular moiety through a sulfonyl group, as defined herein.Representative examples of cycloalkylalkylsulfonyl include, but are notlimited to, cyclopropylmethylsulfonyl, 2-cyclobutylethylsulfonyl,cyclopentylmethylsulfonyl, cyclohexylmethylsulfonyl, and4-cycloheptylbutylsulfonyl.

[0142] The term “cycloalkylcarbonyl,” as used herein, refers to acycloalkyl group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of cycloalkylcarbonyl include, but are not limited to,cyclopropylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.

[0143] The term “cycloalkylcarbonylaryl,” as used herein, refers to acycloalkylcarbonyl group, as defined herein, appended to the parentmolecular moiety through an aryl group, as defined herein.Representative examples of cycloalkylcarbonylaryl include, but are notlimited to, 4-(cyclopropylcarbonyl)phenyl,4-(cyclopentylcarbonyl)phenyl, and 4-(cyclohexylcarbonyl)phenyl.

[0144] The term “cycloalkylcarbonylheterocycle,” as used herein, refersto a cycloalkylcarbonyl group, as defined herein, appended to the parentmolecular moiety through a heterocycle group, as defined herein.Representative examples of cycloalkylcarbonylheterocycle include, butare not limited to, 4-(cyclopropylcarbonyl)-1-piperazinyl,4-(cyclopentylcarbonyl)-1-piperazinyl, and4-(cyclohexylcarbonyl)-1-piperazinyl.

[0145] The term “cycloalkylsulfonyl,” as used herein, refers tocycloalkyl group, as defined herein, appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples of cycloalkylsulfonyl include, but are not limited to,cyclopropylsulfonyl, cyclopentylsulfonyl, and cyclohexylsulfonyl.

[0146] The term “formyl,” as used herein, refers to a —C(O)H group.

[0147] The term “halo” or “halogen,” as used herein, refers to —Cl, —Br,—I or —F.

[0148] The term “haloalkoxy,” as used herein, refers to at least onehalogen, as defined herein, appended to the parent molecular moietythrough an alkoxy group, as defined herein. Representative examples ofhaloalkoxy include, but are not limited to, chloromethoxy,2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

[0149] The term “haloalkyl,” as used herein, refers to at least onehalogen, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhaloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl,trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

[0150] The term “heterocycle” or “heterocyclic,” as used herein, refersto a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ringsystems are exemplified by any 3- or 4-membered ring containing aheteroatom independently selected from oxygen, nitrogen and sulfur; or a5-, 6- or 7-membered ring containing one, two or three heteroatomswherein the heteroatoms are independently selected from nitrogen, oxygenand sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and7-membered ring have from 0-3 double bonds. Representative examples ofmonocyclic ring systems include, but are not limited to, azetidinyl,azepinyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl,furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl,isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl,oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl,thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl,thiazolidinyl, thienyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, triazinyl, triazolyl, andtrithianyl. Bicyclic ring systems are exemplified by any of the abovemonocyclic ring systems fused to an aryl group as defined herein, acycloalkyl group as defined herein, or another monocyclic ring system.Representative examples of bicyclic ring systems include but are notlimited to, for example, benzimidazolyl, benzothiazolyl, benzothienyl,benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl,benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl,indolinyl, indolizinyl, naphthyridinyl, isobenzofuranyl,isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, phthalazinyl,pyranopyridyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridyl.

[0151] The heterocycles of this invention can be substituted with 1,2,or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl,amino, aminoalkyl, aminocarbonyl, aminosulfonyl, carboxy, carboxyalkyl,cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, mercapto, and nitro.

[0152] The term “heterocyclealkyl,” as used herein, refers to aheterocycle, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofheterocyclealkyl include, but are not limited to, pyridin-3-ylmethyl and2-pyrimidin-2-ylpropyl.

[0153] The term “heterocyclealkylcarbonyl,” as used herein, refers to aheterocyclealkyl, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of heterocyclealkylcarbonyl include, but are not limited to,(pyridin-3-ylmethyl)carbonyl and (2-(pyrimidin-2-yl)propyl)carbonyl.

[0154] The term “heterocyclealkylsulfonyl,” as used herein, refers to aheterocyclealkyl, as defined herein, appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples of heterocyclealkylsulfonyl include, but are not limited to,(pyridin-3-ylmethyl)sulfonyl and (2-(pyrimidin-2-yl)propyl)sulfonyl.

[0155] The term “heterocyclearyl,” as used herein, refers to aheterocycle, as defined herein, appended to the parent molecular moietythrough an aryl group, as defined herein. Representative examples ofheterocyclearyl include, but are not limited to, 4-(pyridin-3-yl)phenyland 4-(pyrimidin-2-yl)phenyl.

[0156] The term “heterocyclearylcarbonyl,” as used herein, refers to aheterocyclearyl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of heterocyclearylcarbonyl include, but are notlimited to, 4-(pyridin-3-yl)benzoyl and 4-(pyrimidin-2-yl)benzoyl.

[0157] The term “heterocyclearylsulfonyl,” as used herein, refers to aheterocyclearyl group, as defined herein, appended to the parentmolecular moiety through a sulfonyl group, as defined herein.Representative examples of heterocyclearylsulfonyl include, but are notlimited to, (4-(pyridin-3-yl)phenyl)sulfonyl and(4-(pyrimidin-2-yl)phenyl)sulfonyl.

[0158] The term “heterocyclecarbonyl,” as used herein, refers to aheterocycle, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofheterocyclecarbonyl include, but are not limited to, 2-furoyl,morpholin-1-ylcarbonyl, pyridin-3-ylcarbonyl, pyrrolidin-1-ylcarbonyl,and quinolin-3-ylcarbonyl.

[0159] The term “heterocyclecarbonylaryl,” as used herein, refers to aheterocyclecarbonyl, as defined herein, appended to the parent molecularmoiety through an aryl group, as defined herein. Representative examplesof heterocyclecarbonylaryl include, but are not limited to,4-(2-furoyl)phenyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)phenyl, 4-(1-piperazinylcarbonyl)phenyl and4-(3-pyridinylcarbonyl)phenyl.

[0160] The term “heterocyclecarbonylheterocycle,” as used herein, refersto a heterocyclecarbonyl, as defined herein, appended to the parentmolecular moiety through a heterocycle group, as defined herein.Representative examples of heterocyclecarbonylheterocycle include, butare not limited to, 4-(2-furoyl)-1-piperazinyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)-1-piperazinyl,4-(1-azetidinylcarbonyl)-1-piperazinyl,4-(1-piperazinylcarbonyl)-1-piperazinyl and4-(3-pyridinylcarbonyl)-1-piperazinyl.

[0161] The term “heterocycleheterocycle,” as used herein, refers to aheterocycle group, as defined herein, appended to the parent molecularmoiety through another heterocycle group, as defined herein.Representative examples of heterocycleheterocycle include, but are notlimited to, 2-(pyridin-3-yl)thiazo-4-yl and2-(pyrimidin-2-yl)thiazo-4-yl.

[0162] The term “heterocycleheterocyclecarbonyl,” as used herein, refersto a heterocycleheterocycle group, as defined herein, appended to theparent molecular moiety through a carbonyl group, as defined herein.Representative examples of heterocycleheterocyclecarbonyl include, butare not limited to, (2-(pyridin-3-yl)thiazo-4-yl)carbonyl and(2-(pyrimidin-2-yl)thiazo-4-yl)carbonyl.

[0163] The term “heterocycleheterocyclesulfonyl,” as used herein, refersto a heterocycleheterocycle group, as defined herein, appended to theparent molecular moiety through a sulfonyl group, as defined herein.Representative examples of heterocycleheterocyclesulfonyl include, butare not limited to, (2-(pyridin-3-yl)thiazo-4-yl)sulfonyl and(2-(pyrimidin-2-yl)thiazo-4-yl)sulfonyl.

[0164] The term “heterocycleoxy,” as used herein, refers to aheterocycle group, as defined herein, appended to the parent molecularmoiety through an oxy moiety, as defined herein. Representative examplesof heterocycleoxy include, but are not limited to, pyrid-3-yloxy andquinolin-3-yloxy.

[0165] The term “heterocycleoxyalkyl,” as used herein, refers to aheterocycleoxy group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of heterocycleoxyalkyl include, but are notlimited to, pyrid-3-yloxymethyl and 2-quinolin-3-yloxyethyl.

[0166] The term “heterocycleoxyalkylcarbonyl,” as used herein, refers toa heterocycleoxyalkyl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of heterocycleoxyalkylcarbonyl include, but arenot limited to, (pyridin-3-yloxymethyl)carbonyl and(2-(quinolin-3-yloxy)ethyl)carbonyl.

[0167] The term “heterocycleoxyaryl,” as used herein, refers to aheterocycleoxy group, as defined herein, appended to the parentmolecular moiety through an aryl group, as defined herein.Representative examples of heterocycleoxyaryl include, but are notlimited to, 4-(pyridin-3-yloxy)phenyl and 4-(quinolin-3-yloxy)phenyl.

[0168] The term “heterocycleoxyarylcarbonyl,” as used herein, refers toa heterocycleoxyaryl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of heterocycleoxyarylcarbonyl include, but arenot limited to, 4-(pyridin-3-yloxy)benzoyl and4-(quinolin-3-yloxy)benzoyl.

[0169] The term “heterocycleoxyarylsulfonyl,” as used herein, refers toa heterocycleoxyaryl group, as defined herein, appended to the parentmolecular moiety through a sulfonyl group, as defined herein.Representative examples of heterocycleoxyarylsulfonyl include, but arenot limited to, (4-(pyridin-3-yloxy)phenyl)sulfonyl and(4-(quinolin-3-yloxy)phenyl)sulfonyl.

[0170] The term “heterocyclesulfonyl,” as used herein, refers to aheterocycle group, as defined herein, appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples of heterocyclesulfonyl include, but are not limited to,(pyridin-3-yl)sulfonyl and (quinolin-8-yl)sulfonyl.

[0171] The term “heterocyclethio,” as used herein, refers to aheterocycle group, as defined herein, appended to the parent molecularmoiety through a thio moiety, as defined herein. Representative examplesof heterocyclethio include, but are not limited to, pyrid-3-ylsulfanyland quinolin-3-ylsulfanyl.

[0172] The term “heterocyclethioalkyl,” as used herein, refers to aheterocyclethio group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of heterocyclethioalkyl include, but are notlimited to, pyrid-3-ylsulfanylmethyl,(4-methylpyrimidin-2-yl)sulfanylmethyl, and2-(quinolin-3-ylsulfanyl)ethyl.

[0173] The term “heterocyclethioalkylcarbonyl,” as used herein, refersto a heterocyclethioalkyl group, as defined herein, appended to theparent molecular moiety through a carbonyl group, as defined herein.Representative examples of heterocyclethioalkylcarbonyl include, but arenot limited to, (pyrid-3-ylsulfanyl)acetyl,((4-methylpyrimidin-2-yl)sulfanyl)acetyl, and(quinolin-3-ylsulfanyl)acetyl.

[0174] The term “hydroxy,” as used herein, refers to an —OH group.

[0175] The term “hydroxyalkyl,” as used herein, refers to one or twohydroxy groups, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of hydroxyalkyl include, but are not limited to, ishydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl and2-ethyl-4-hydroxyheptyl.

[0176] The term “lower alkyl,” as used herein, is a subset of alkyl asdefined herein and refers to a straight or branched chain hydrocarbongroup containing from 1 to 4 carbon atoms. Examples of lower alkyl aremethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andtert-butyl.

[0177] The term “mercapto,” as used herein, refers to a —SH group.

[0178] The term “nitro,” as used herein, refers to a —NO₂ group.

[0179] The term “oxo,” as used herein, refers to a ═O moiety.

[0180] The term “oxy,” as used herein, refers to a —O— moiety.

[0181] The term “phosphono,” as used herein, refers to a —P(O)(OR_(D))₂group wherein R_(D) is selected from hydrogen and alkyl, as definedherein. Representative examples of phosphono include, but are notlimited to, dimethoxyphosphoryl and diethoxyphosphoryl.

[0182] The term “sulfinyl,” as used herein, refers to a —S(O)— group.

[0183] The term “sulfono,” as used herein, refers to a —S(O)₂(ORE) groupwherein R_(E) is selected from alkyl, aryl, and arylalkyl, as definedherein. Representative examples of sulfono include, but are not limitedto, methoxysulfonyl, ethoxysulfonyl, (benzyloxy)sulfonyl andphenoxysulfonyl.

[0184] The term “sulfonyl,” as used herein, refers to a —SO₂— group.

[0185] The term “thio,” as used herein, refers to a —S— moiety.

[0186] Preferred compounds of formula I include, but are not limited to:

[0187] N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}cyclopropanecarboxamide;

[0188] N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-[(4-methyl-2-pyrimidinyl)sulfanyl]acetamide;

[0189] N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl }nicotinamide;

[0190]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;

[0191]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-cyanobenzenesulfonamide;

[0192]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-propanesulfonamide;

[0193] 1-(4-{3-[(3R)-3-aminopyrrolidinyl]propoxy }phenyl)-1-propanone;

[0194](5R)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedione;

[0195](5S)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedione;

[0196](5R)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-isopropyl-2,4-imidazolidinedione;

[0197] 4-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0198]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-propanesulfonamide;

[0199]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;

[0200]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-cyanobenzamide;

[0201]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0202]4-bromo-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0203]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;

[0204]4-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0205]N-(4-{[((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;

[0206]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methoxybenzenesulfonamide;

[0207]4-tert-butyl-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0208]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;

[0209]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;

[0210]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2,5-dimethoxybenzenesulfonamide;

[0211]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-methylbenzenesulfonamide;

[0212]3-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;

[0213]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-ethylbenzenesulfonamide;

[0214]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-isopropylbenzenesulfonamide;

[0215]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-fluorobenzenesulfonamide;

[0216]2-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0217]3-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0218]3,5-dichloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0219]4-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0220]3-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0221]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-1-methyl-1H-imidazole-4-sulfonamide;

[0222]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-thiophenesulfonamide;

[0223]5-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-methyl-1-benzothiophene-2-sulfonamide;

[0224]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,5-bis(trifluoromethyl)benzenesulfonamide;

[0225]N-(5-{[((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}-4-methyl-1,3-thiazol-2-yl)acetamide;

[0226]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-8-quinolinesulfonamide;

[0227]4-butoxy-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0228]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,4-dimethoxybenzenesulfonamide;

[0229]3-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;

[0230]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-phenylethenesulfonamide;

[0231]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-(trifluoromethoxy)benzenesulfonamide;

[0232]2-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0233]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-methylbenzenesulfonamide;

[0234]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;

[0235]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-fluorobenzenesulfonamide;

[0236]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0237]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2,4-difluorobenzenesulfonamide;

[0238]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-7-isoquinolinesulfonamide;

[0239]N-(2-chloro-4-{[((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxylpropyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;

[0240]3,4-dichloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0241]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0242]4-bromo-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0243]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;

[0244]4-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0245]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methoxybenzenesulfonamide;

[0246]4-tert-butyl-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0247]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;

[0248]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-(trifluoromethyl)benzenesulfonamide;

[0249]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2,5-dimethoxybenzenesulfonamide;

[0250]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-methylbenzenesulfonamide;

[0251]3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;

[0252]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-ethylbenzenesulfonamide;

[0253]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-isopropylbenzenesulfonamide;

[0254]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-fluorobenzenesulfonamide;

[0255]2-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0256] 3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0257]3-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0258]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrolidinyl}-3-fluorobenzenesulfonamide;

[0259]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-(trifluoromethoxy)benzenesulfonamide;

[0260]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2,4-difluorobenzenesulfonamide;

[0261]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-isoquinolinesulfonamide;

[0262]N-{4-[({(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}amino)sulfonyl]-2-chlorophenyl}acetamide;

[0263]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-3,4-dichlorobenzenesulfonamide;

[0264]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1H-pyrrole-2-sulfonamide;

[0265]N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}benzenesulfonamide;

[0266]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-1-methyl-1H-imidazole-4-sulfonamide;

[0267]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-thiophenesulfonamide;

[0268]5-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-methyl-1-benzothiophene-2-sulfonamide;

[0269]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3,5-bis(trifluoromethyl)benzenesulfonamide;

[0270]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-8-quinolinesulfonamide;

[0271]4-butoxy-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0272]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3,4-dimethoxybenzenesulfonamide;

[0273]3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;

[0274]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-phenylethenesulfonamide;

[0275]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-(trifluoromethoxy)benzenesulfonamide;

[0276]2-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0277]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-methylbenzenesulfonamide;

[0278]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;

[0279]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-fluorobenzenesulfonamide;

[0280]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-(trifluoromethoxy)benzenesulfonamide;

[0281]N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-8-isoquinolinesulfonamide;

[0282]N-(2-chloro-4-{[((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;

[0283]3,4-dichloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0284] tert-butyl1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}-3-pyrrolidinylcarbamate;

[0285]4′-{3-[(3R)-3-aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;

[0286] tert-butyl(3S)-1-{2-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]ethyl}pyrrolidinylcarbamate;

[0287]4-methoxy-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0288]4-isopropyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0289]4-cyano-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0290]3-cyano-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0291]1-methyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)-1H-imidazole-4-sulfonamide;

[0292]3,4-dimethoxy-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;

[0293]N-(2-chloro-4-{[((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;

[0294]4′-{3-[(3R)-3-(dimethylamino)pyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;

[0295] tert-butyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;

[0296]4′-{3-[(3R)-3-(methylamino)pyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;

[0297]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylacetamide;

[0298]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,3,3-trimethylbutanamide;

[0299] methyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;

[0300]tert-pentyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;

[0301]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N′,N′-trimethylurea;

[0302]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-1-pyrrolidinecarboxamide;

[0303]N′-tert-butyl-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylurea;

[0304]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-4-morpholinecarboxamide;

[0305]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluoro-N-methylbenzamide;

[0306]4-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylbenzamide;

[0307]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylnicotinamide;

[0308]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-2-furamide;

[0309]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;

[0310]N-[(3R)-1-[3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl]pyrrolidinyl]-N,N′,N′-trimethyl-sulfamide;

[0311]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-fluoro-N-methylbenzenesulfonamide;

[0312]4-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylbenzenesulfonamide;

[0313]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-isopropyl-N-methylbenzenesulfonamide;

[0314]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-4-(methylsulfonyl)benzenesulfonamide;

[0315]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluoro-N-(4-fluorobenzoyl)benzamide;

[0316]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)acetamide;

[0317]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,3-dimethylbutanamide;

[0318] allyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;

[0319] methyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;

[0320] tert-pentyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;

[0321]N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N-dimethylurea;

[0322]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-1-pyrrolidinecarboxamide;

[0323]N-(tert-butyl)-N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)urea;

[0324]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-morpholinecarboxamide;

[0325]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzamide;

[0326]4-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzamide;

[0327]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)nicotinamide;

[0328]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxyjpropyl}pyrrolidinyl)-2-furamide;

[0329]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;

[0330]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-propanesulfonamide;

[0331] N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N-dimethylsulfamide;

[0332]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(methylsulfonyl)benzenesulfonamide;

[0333]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(3,3-dimethylbutanoyl)-3,3-dimethylbutanamide;

[0334]N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N′-(dimethylaminocarbonyl)-N,N-dimethylurea;

[0335] N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propylpyrrolidinyl)-N-(1-pyrrolidinylcarbonyl)-1-pyrrolidinecarboxamide;

[0336]N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(4-morpholinylcarbonyl)-4-morpholinecarboxamide;

[0337] cyclopropyl{4-[3-(3-hydroxy-1-pyrrolidinyl)propoxy]phenyl}methanone;

[0338]cyclopropyl(4-{3-[(3R)-3-hydroxypyrrolidinyl]propoxy}phenyl)methanone;

[0339]4′-{3-[(3R)-3-hydroxypyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;

[0340]4′-[3-(3-oxo-1-pyrrolidinyl)propoxy][1,1′-biphenyl]-4-carbonitrile;

[0341]4′-{3-[(3S)-3-hydroxypyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;

[0342]4′-[3-(3-hydroxy-3-methyl-1-pyrrolidinyl)propoxy[1,1′-biphenyl]-4-carbonitrile;

[0343]4′-[3-(3-hydroxy-3-isopropyl-1-pyrrolidinyl)propoxy][1,1′-biphenyl]-4-carbonitrile;

[0344]4′-{3-[(3R)-3-hydroxy-3-methylpyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;

[0345]N,N-dimethyl-N-[(3R)-1-(3-{[4′-(1-pyrrolidinylcarbonyl)[1,1′-biphenyl]-4-yl]oxy}propyl)pyrrolidinyl]amine;

[0346]N,N-dimethyl-N-[(3S)-1-(3-{[4′-(1-pyrrolidinylcarbonyl)[1,1′-biphenyl]-4-yl]oxy}propyl)pyrrolidinyl]amine;

[0347](3R)-1-(3-{[4′-(1-pyrrolidinylcarbonyl)[1,1′-biphenyl]-4-yl]oxy}propyl)-3-pyrrolidinol;

[0348]N,N-dimethyl-N-[(3R)-1-(3-{4-[4-(1-pyrrolidinylcarbonyl)-1-piperazinyl]phenoxy}propyl)pyrrolidinyl]amine;

[0349]N,N-dimethyl-N-[(3S)-1-(3-{4-[4-(1-pyrrolidinylcarbonyl)-1-piperazinyl]phenoxy}propyl)pyrrolidinyl]amine;

[0350]4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1′-biphenyl-4-carbonitrile;

[0351]4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2-methyl-1,1′-biphenyl-4-carbonitrile;

[0352]4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-fluoro-1,1′-biphenyl-4-carbonitrile;

[0353]4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-fluoro-1,1′-biphenyl-4-carbonitrile;

[0354] b 4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-methyl-1,1′-biphenyl-4-carbonitrile;

[0355]4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-iodo-1,1′-biphenyl-4-carbonitrile;

[0356]4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2′-methyl-1,1′-biphenyl-4-carbonitrile;

[0357]3′-chloro-4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-1,1′-biphenyl-4-carbonitrile;

[0358]4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′,5′-difluoro-1,1′-biphenyl-4-carbonitrile;

[0359]4′-(3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-methoxy-1,1′-biphenyl-4-carbonitrile;

[0360]3′-chloro-4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-5′-fluoro-1,1′-biphenyl-4-carbonitrileand pharmaceutically acceptable salts, esters, amides, or prodrugsthereof.

[0361] Abbreviations

[0362] Abbreviations which have been used in the descriptions of theschemes and the examples that follow are: AcOH for acetic acid; BF₃OEt₂for boron trifluoride diethyl ether complex; Boc fortert-butoxycarbonyl; (Boc)₂O for di-tert-butyl dicarbonate; n-BuLi forn-butyllithium; CDI for 1,1′-carbonyldiimidazole; DCC for1,3-dicyclohexylcarbodiimide; DMAP for 4-dimethylaminopyridine; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; EDCI or EDC for1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; EtOAcfor ethyl acetate; EtOH for ethanol; HOBT for 1-hydroxybenzotriazolehydrate; IPA for isopropanol; LAH for lithium aluminum hydride; LDA forlithium diisopropylamide; MeOH for methanol; Ph for phenyl; pyr forpyridine; TFA for trifluoroacetic acid; and THF for tetrahydrofuran.

[0363] Preparation of Compounds of the Invention

[0364] The compounds and processes of the present invention will bebetter understood in connection with the following synthetic schemes andmethods which illustrate a means by which the compounds of the inventioncan be prepared.

[0365] The compounds of this invention can be prepared by a variety ofsynthetic routes. Representative procedures are shown in Schemes 1-7.

[0366] Sulfonamides of general formula (6), wherein R₃, R₈, R_(A),R_(B), R_(C) and R_(D) are as defined in formula I, and R₁₀ is selectedfrom alkenyl, alkyl, alkynyl, amino, aryl, arylalkenyl, arylalkyl,arylaryl, arylheterocyle, aryloxyaryl, cycloalkyl, cycloalkylalkyl,heterocyclealkyl, heterocyclearyl, heterocycleheterocycle,heterocycleoxyaryl or heterocycle, may be prepared as described inScheme 1. Typically, a compound of general formula (I) can be preparedby a coupling reaction in the presence of a transition metal catalystsuch as tetrakis(triphenylphosphine) palladium and a base such aspotassium carbonate or cesium carbonate under standard Suzuki, Stille orHeck coupling conditions well known to those of skill in the art.Phenols of general formula (1), obtained commercially or prepared usingstandard methodology known to those of skill in the art, may be treatedwith 1-bromo-3-chloropropane (or 1-bromo-2-chloroethane to provide theethyl analogues) and a base such as potassium carbonate in a solventsuch as 2-butanone with heat to provide chlorides of general formula(2). Chlorides of general formula (2) may be treated with tert-butylpyrrolidinylcarbamate (or tert-butyl (3R)-pyrrolidinylcarbamate ortert-butyl (3S)-pyrrolidinylcarbamate), potassium iodide, a base such aspotassium carbonate in a solvent such as 2-butanone with heat to provideN-boc aminopyrrolidines which may be deprotected with acid such as 4NHCl in 1,4-dioxane or trifluoroacetic acid in CH₂Cl₂ to provideaminopyrrolidines of general formula (3). Aminopyrrolidines of generalformula (3) may be treated with sulfonyl chlorides of general formula(4), a base such as triethylamine, diisopropylamine or a polymersupported base such as tris(2-aminoethyl)amine-polystyrene resin andcatalytic DMAP in a solvent such as methylene chloride or DMF to providesulfonamides of general formula (5). Sulfonamides of general formula (5)may be treated with a base such as sodium hydride and an electrophilesuch as, for example, iodomethane, allyl bromide or propargyl bromide toprovide sulfonamides of general formula (6).

[0367] Amides of general formula (9), wherein R₃, R₉, R_(A), R_(B),R_(C) and R_(D) are as defined in formula I and R₁₁ is selected fromhydrogen, alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, alkynyloxy,amino, arylalkenyl, arylalkyl, arylaryl, aryl, arylheterocyle,aryloxyaryl, cycloalkylalkyl, cycloalkyl, heterocyclealkyl,heterocyclearyl, heterocycle, heterocycleheterocycle,heterocycleoxyalkyl, heterocycleoxyaryl, and heterocyclethioalkyl, maybe prepared as described in Scheme 2. Aminopyrrolidines of generalformula (3), from Scheme 1, may be treated with acids of general formula(7), a coupling reagent such as DCC, EDCI, or a polymer supportedcoupling reagent (N-cyclohexylcarbodiimide, N′-methyl polystyreneresin), catalytic DMAP, a base such as triethylamine, diisopropylamineor a polymer supported base (tris(2-aminoethyl)amine-polystyrene resin)and optionally HOBT to provide amides of general formula (8).Alternatively, aminopyrrolidines of general formula (3) may be treatedwith acid chlorides and a base to provide amides of general formula (8).Amides of general formula (8) may be treated with a base such as sodiumhydride and an electrophile such as, for example, iodomethane, allylbromide, propargyl bromide or an acid chloride to provide amides ofgeneral formula (9).

[0368] Amines of general formula (10) and (11), wherein R₈, R_(A),R_(B), R_(C) and R_(D) are as defined in formula I and R₃ and R₄ areindependently selected from alkenyl, alkyl, alkynyl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocycle and heterocyclealkyl, may beprepared as described in Scheme 3. Aminopyrrolidines of general formula(3), from Scheme 1, may be treated with electrophiles such as, forexample, iodomethane, allyl bromide, propargyl bromide, benzylbromide,bromocyclohexane or 3,6-dichloropyridazine and a base such astriethylamine or diisopropylamine in a solvent such as DMF or THF toprovide monosubstituted amines of general formula (10). Monosubstitutedamines of general formula (10) may be retreated with an electrophile anda base to provide disubstituted amines of general formula (11).

[0369] 2,5-Dioxo-1-imidazolidines of general formula (15) and (16),wherein R₅, R₆, R₉, R_(A), R_(B), R_(C) and R_(D) are as defined informula I, may be prepared as described in Scheme 4. Aminopyrrolidinesof general formula (3), from Scheme 1, may be treated with N-protected(L) α-amino acids or N-protected (D) α-amino acids of general formula(13), a coupling reagent such as DCC or EDCI and 1-hydroxybenzotriazolehydrate (HOBT) in a solvent such as DMF or methylene chloride to provideamides of general formula (14). Amides of general formula (14) may bedeprotected with acid such as 4N HCl in 1,4-dioxane or trifluoroaceticacid in methylene chloride and then treated with 1,1-carbonyldiimidazole(CDI) and a base such as triethylamine or diisopropylamine in a solventsuch as acetonitrile to provide 2,5-dioxo-1-imidazolidines of generalformula (15). 2,5-Dioxo-1-imidazolidines of general formula (15) may betreated with a base such as sodium hydride and an alkyl halide toprovide 2,5-dioxo-1-imidazolidines of general formula (16).

[0370] Alkoxy pyrrolidines of general formula (21), wherein R₂, R₉,R_(A), R_(B), R_(C) and R_(D) are as defined in formula I, may beprepared as described in Scheme 5. Chlorides of general formula (2),from Scheme 1, may be treated with 3-hydroxypyrrolidine (or(3R)-hydroxypyrrolidine or (3S)-hydroxypyrrolidine), a base such aspotassium carbonate, and potassium iodide in a solvent such as2-butanone with heat to provide hydroxy pyrrolidines of general formula(20). Hydroxy pyrrolidines of general formula (20) may be treated with abase such as sodium hydride and alkyl halides, acid chlorides, carbamylchlorides, sulfonyl chlorides or chlorophosphates in a solvent such asTHF or DMF to provide alkoxy pyrrolidines of general formula (21).

[0371] Alkoxy pyrrolidines of general formula (26), wherein R₂, R₇, R₈,R_(A), R_(B), R_(C) and R_(D) are as defined in formula I, may beprepared as described in Scheme 6. Chlorides of general formula (2),from Scheme 1, may be treated with 3-pyrrolidinone, a base such aspotassium carbonate, and potassium iodide in a solvent such as2-butanone with heat to provide ketones of general formula (24). Ketonesof general formula (24) may be treated with alkyl halides, magnesiummetal and 1,2-dibromoethane (or ketones of general formula (24) may betreated with an alkyllithium reagent) in a solvent such as THF ordiethyl ether to provide tertiary alcohols of general formula (25).Tertiary alcohols of general formula (25) may be treated with a basesuch as sodium hydride and an alkyl halide in a solvent such as THF orDMF to provide alkoxy pyrrolidines of general formula (26).

[0372] 3-Substituted pyrrolidines of general formula (33), wherein R₁,R₇, R₈, R₉, R_(A), R_(B), R_(C) and R_(D) are as defined in formula 1,may be prepared as described in Scheme 7. Phenols of general formula(1), from Scheme 1, may be treated with haloketones of general formula(30), a base such as potassium carbonate, and potassium iodide in asolvent such as 2-butanone with heat to provide ketones of generalformula (31). Ketones of general formula (31) may be treated with sodiumcyanoborohydride under acidic conditions (or other standardreductive-amination conditions) to provide 3-substituted pyrrolidines ofgeneral formula (33).

[0373] Schemes 1-7 exemplify preparation of compounds of the presentinvention wherein Z, as defined in formula I, is CH₂. Compounds of thepresent invention wherein Z, as defined in formula I, is a covalent bondmay be prepared by using the methods described in schemes 1-7 andsubstituting 1-bromo-2-chloroethane for 1-bromo-3-chloropropane.

[0374] The compounds and processes of the present invention will bebetter understood by reference to the following examples, which areintended as an illustration of and not a limitation upon the scope ofthe invention. Further, all citations herein are incorporated byreference.

EXAMPLE 1 N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}cyclopropanecarboxamide

[0375] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone (0.05g, 0.19 mmol) in dichloromethane (2 mL) was treated with cyclopropanecarboxylic acid (0.025 g, 0.29 mmol) followed byN-cyclohexylcarbodiimide, N′-methyl polystyrene resin (0.15 g, 0.29mmol, 2mmol/g loading) and catalytic N,N-dimethylaminopyridine. Aftershaking at ambient temperature for 14 hours, the mixture was treatedwith tris-(2-aminoethyl)-amine-polystyrene (0.063 g, 0.19 mmol, 3 mmol/gloading) resin and the reaction mixture shaken for an additional 2hours. The mixture was filtered and the filtrate was concentrated. Theresidue was purified using reverse phase HPLC to afford 0.04 g (63 %) ofthe title compound.

[0376] MS (ESI+) m/z 331 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.2 (d, 1H), 7.9 (d, 2 H), 7.00 (d, 2 H), 4.2 (m, 1 H), 4.15 (t, 2 H), 2.7-2.8(m, 2 H), 2.5 (m, 2 H), 2.2 (m, 2 H), 1.9 (s, 3 H), 1.8 (m, 2 H), 1.6(m, 2 H), 0.6 (m, 4 H).

EXAMPLE 2N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-[(4-methyl-2-pyrimidinyl)sulfanyl]acetamide

[0377] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and[(4-methyl-2-pyrimidinyl)sulfanyl]acetic acid were processed asdescribed in Example 1 to provide the title compound.

[0378] MS (ESI+) m/z 429 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.4 (d, 2H), 8.2 (d, 1 H), 7.8 (d, 2 H), 7.0 (d, 2 H), 6.92 (d, 2 H), 4.15 (m, 3H), 3.7 (s, 2 H), 2.65-2.7 (m, 2 H), 2.3 (s, 3 H), 2.25 (m, 2 H), 2.0(m, 2 H), 1.90 (s, 3 H), 1.85 (m, 2 H), 1.6 (m, 2 H).

EXAMPLE 3 N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}nicotinamide

[0379] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone andnicotinic acid were processed as described in Example 1 to provide thetitle compound.

[0380] MS (ESI+) m/z 368 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.0 (s, 1H), 8.6 (d, 1 H), 8.55 (d, 1 H), 8.1 (d, 1 H), 7.8 (d, 2 H), 7.4 (d, 1H), 7.0 (d, 2 H), 4.25 (m, 1H), 4.0 (t, 2 H), 2.8 (t, 2 H), 2.6 (m, 2H), 2.2 (m, 2 H), 1.95 (m, 2 H), 1.8 (s, 3 H), 1.75 (m, 2 H).

EXAMPLE 4N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide

[0381] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and2-(3-pyridinyl)-1,3-thiazole-4-carboxylic acid were processed asdescribed in Example 1 to provide the title compound.

[0382] MS (ESI+) m/z 451 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 8.7 (d, 1 H), 8.4 (m, 2 H), 7.90 (d, 2 H), 7.6 (m, 2 H), 7.0 (d, 2H), 4.25 (m, 1H), 4.2 (t, 2 H), 2.8 (m, 2 H), 2.6 (m, 2 H), 2.2 (m, 2H), 2.0 (m, 2 H), 1.95 (s, 3 H), 1.8 (m, 2H).

EXAMPLE 5N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-cyanobenzenesulfonamide

[0383] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and4-cyanobenzenesulfonyl chloride were processed as described in Example20 to provide the title compound.

EXAMPLE 6N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-propanesulfonamide

[0384] 1-(4-{3-[(3R)-3-aminopyrrolidinyl]propoxy}phenyl)ethanone and2-propanesulfonyl chloride were processed as described in Example 20 toprovide the title compound.

EXAMPLE 7 1-(4-{3-[(3R)-3-aminopyrrolidinyl]propoxy}phenyl)-1-propanone

[0385] 1-(4-Hydroxyphenyl)-1-propanone was processed as described inExamples 9A-C to provide the title compound.

[0386] MS (ESI+) m/z 276 (M+H)⁺; ¹H NMR (300 MHz, D₂O) δ 8.0 (d, 2 H),7.0 (d, 2 H), 4.25 (m, 3 H), 3.8 (br s, 2 H), 3.6 (m, 2 H), 3.0 (q, 2H), 2.8 (br s, 2 H), 2.2 (m, 2 H), 1.1 (t, 3 H).

EXAMPLE 8(5R)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedione

[0387] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and(2R)-2-[(tert-butoxycarbonyl)amino]propanoic acid were processed asdescribed in Examples 9D-F to provide the title compound.

[0388] MS (ESI+) m/z 360 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.2 (br s,1 H), 7.9 (d, 2 H), 7.0 (d, 2 H), 4.4 (m, 1 H), 4.15 (t, 2 H), 4.0 (m,1H), 2.85 (m, 2 H), 2.8 (m, 2 H), 2.6 (m, 2 H), 2.0 (m, 2 H), 1.9 (s, 3H), 1.4 (m, 2 H), 1.2 (d, 3 H).

EXAMPLE 9(5S)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedioneEXAMPLE 9A 1-[4-(3-chloropropoxy)phenyl]ethanone

[0389] 1-(4-hydroxyphenyl)ethanone, 1-bromo-3-chloropropane andpotassium carbonate were processed as described in Example 67B toprovide the title compound which was used in the next step withoutfurther purification.

EXAMPLE 9B tert-butyl(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinylcarbamate

[0390] 1-[4-(3-Chloropropoxy)phenyl]ethanone (1.00 g, 4.7 mmol) inacetone (35 mL), was treated with potassium carbonate (0.97 g, 7.05mmol), tert-butyl (3R)-pyrrolidinylcarbamate (0.88 g, 4.7 mmol) andpotassium iodide (0.78 g, 4.7 mmol). After heating the reaction mixtureat reflux for 24 hours, the acetone was evaporated and 50 mLdichloromethane was added. The organic layer was washed with water (3×15mL) and then concentrated under reduced pressure to provide the titlecompound which was used in the next step without further purification.

EXAMPLE 9C 1-(4-{3-[(3R)-3-aminopyrrolidinyl]propoxy}phenyl)ethanone

[0391] tert-Butyl(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinylcarbamate, from Example9B, in dichloromethane (25 mL) was treated with trifluoroacetic acid (5mL). After stirring for 2 hours, the mixture was treated with 2N NaOH.The organic layer was collected, dried over MgSO₄, filtered andconcentrated under reduced pressure to provide the title compound as abrown oil (1.2 g).

[0392] MS (ESI+) m/z 263 (M+H)⁺; ¹H NMR (300 MHz, D₂O) δ 8.00 (d, 2 H),7.00 (d, 2 H), 4.2 (t, 2 H), 3.3 (m, 2 H), 3.0 (m, 2 H), 2.5-2.8 (m, 5H), 2.44 (s, 3 H), 2.1 (m, 2 H); ¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (d,2H), 7.05 (d, 2H), 4.3 (t, 2H), 3.6 (m, 1H), 2.55 (m, 1H), 2.49 (s, 3H),2.4-2.3 (m, 4H), 2.2 (m, 1H), 1.8-1.6 (m, 2H), 1.4 (m, 2H).

EXAMPLE 9D tert-butyl (1S)-2-({(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}amino)-1-methyl-2-oxoethylcarbamate

[0393] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone (0.1 g,0.38 mmol) in anhydrous dichloromethane (10 mL), was treated with(2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid (0.11 g, 0.40 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.077 g,0.40 mmol) and 1-hydroxybenzotriazole (0.05 g, 0.40 mmol). Afterstirring at ambient temperature for 12 hours, the mixture was treatedwith water (20 mL) and the two phases were separated. The aqueous layerwas extracted with dichloromethane (3×15 mL). All the organics werecombined, dried over MgSO₄ and evaporated under reduced pressure toprovide the title compound which was used for the subsequent stepwithout further purification.

EXAMPLE 9E(2S)-N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-aminopropanamide

[0394] tert-Butyl (1S)-2-({(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}amino)-1-methyl-2-oxoethylcarbamate,from Example 9D, was treated with a 10% solution of TFA indichloromethane (30 mL). After stirring for 2 hours, the mixture wastreated with water and the aqueous portion adjusted to pH=8 using 2NNaOH. The organic layer was separated and the aqueous layer extractedwith ethyl acetate (3×20 mL). All the organic layers were combined,dried over MgSO₄, filtered and evaporated under reduced pressure toprovide the title compound.

EXAMPLE 9F(5S)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedione

[0395](2S)-N-{(3R)-1-[3-(4-Acetylphenoxy)propyl]pyrrolidinyl}-2-aminopropanamidein acetonitrile (25 mL) was treated with 1,1′-carbonyldiimidazole (0.05g, 0.34 mmol) and triethylamine (0.07 g, 0.68 mmol). After heating at40° C. for 16 hours, the mixture was allowed to cool to ambienttemperature and the solvent was evaporated under reduced pressure. Theresidue was purified via reverse-phase silica gel chromatography using aC18 column, to provide 0.07 g (49 %) of the title compound.

[0396] MS (ESI+) m/z 360 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.2 (br s,1 H), 7.9 (d, 2 H), 7.0 (d, 2 H), 4.4 (m, 1 H), 4.15 (t, 2 H), 3.95 (m,1H), 2.8 (m, 3 H), 2.51(, 4 H), 2.1 (m, 2 H), 1.8 (m, 2 H), 1.4 (m, 2H), 1.1 (d, 3 H).

EXAMPLE 10(5R)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-isopropyl-2,4-imidazolidinedione

[0397] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid were processedas described in Examples 9D-F to provide the title compound.

EXAMPLE 114-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0398](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-cyanobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 12N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-propanesulfonamide

[0399](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2-propanesulfonyl chloride were processed as described in Example 20to provide the title compound.

EXAMPLE 13N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxyl]propyl}pyrrolidinyl)-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide

[0400] (4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanone and2-(3-pyridinyl)-1,3-thiazole-4-carboxylic acid were processed asdescribed in Example 1 to provide the title compound.

EXAMPLE 14N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-cyanobenzamide

[0401] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and4-cyanobenzoic acid were processed as described in Example 1 to providethe title compound.

[0402] MS (ESI+) m/z 392 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.00 (d, 2H), 7.8-7.9 (m, 4 H), 7.00 (d, 2 H), 4.4 (m, 1 H), 4.15 (m, 2 H), 2.8(m, 2 H), 2.5-2.7 (m, 4 H), 2.2 (m, 2 H), 1.95 (s, 3 H), 1.8 (m, 2 H).

EXAMPLE 15N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0403] 4′-{3-[(3R)-3-Arninopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile and benzenesulfonyl chloride wereprocessed as described in Example 20 to provide the title compound.

EXAMPLE 164-bromo-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0404]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-bromobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 17N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide

[0405]4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-fluorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 184-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0406]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-chlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 19N-(4-{[((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide

[0407]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-(acetylamino)benzenesulfonyl chloride were processed as describedin Example 20 to provide the title compound.

EXAMPLE 20N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methoxybenzenesulfonamide

[0408]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(0.05 g, 0.15 mmol) in dichloromethane (2 mL) was treated with polymersupported N,N-diisopropylethylamine (0.10 g, 0.31 mmol, 3mmol/gloading), catalytic N,N-dimethylaminopyridine, and4-methoxybenzenesulfonyl chloride (0.034 g, 0.17 mmol). After shaking atambient temperature for 14 hours, the mixture was treated withtris-(2-aminoethyl)-amine-polystyrene (0.05 g, 0.15 mmol, 3 mmol/gloading) resin and the reaction mixture shaken for an additional 2hours. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified using reverse phase HPLC toafford 0.053 g (79%) of the title compound.

[0409] MS (ESI+) m/z 492 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (m, 4H), 7.7 (m, 4 H), 7.0 (m, 4 H), 4.0 (t, 2 H), 3.8 (s, 3 H), 3.6 (m, 1H), 2.4-2.6 (m, 4 H), 2.2 (m, 1 H), 1.8(m, 4 H), 1.5 (m, 1 H).

EXAMPLE 214-tert-butyl-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0410]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-tert-butylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 22N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide

[0411]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-methylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 23N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide

[0412]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-(trifluoromethyl)benzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 24N-((3R)-1-{3-[(4-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2,5-dimethoxybenzenesulfonamide

[0413]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}1,1′-biphenyl]-4-carbonitrileand 2,5-dimethoxybenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 25N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-methylbenzenesulfonamide

[0414]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2-methylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

[0415] MS (ESI+) m/z 476 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.8 (m, 4H), 7.7 (d, 2 H), 7.4 (m, 4 H), 7.0 (d, 2 H), 4.4 (s, 3 H), 4.0 (t, 2H), 3.7 (m, 1 H), 2.8 (m, 1 H), 2.5 (m, 4 H), 2.2 (m, 1H), 2.0 (m, 1 H),1.9 (m, 2 H), 1.6 (m, 1 H).

EXAMPLE 263-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide

[0416]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3-chloro-4-fluorobenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 27N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-ethylbenzenesulfonamide

[0417]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-ethylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 28 N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-isopropylbenzenesulfonamide

[0418]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-(2-propyl)benzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 29 N-((3R)-1-{3-[(4′-cyano[l1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-fluorobenzenesulfonamide

[0419]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2-fluorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 302-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0420]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2-chlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 313-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0421]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3-chlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 323,5-dichloro-N-((3R)-1-{3-F(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0422]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3,5-dichlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 334-cyano-N-((3R)-1-{3-F(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0423]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-cyanobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 343-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxylpropyl}pyrrolidinyl)benzenesulfonamide

[0424]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3-cyanobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

[0425] MS (ESI+) m/z 487 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.2 (s, 1H), 8.1 (d, 2 H), 7.8 (m, 5 H), 7.6 (d, 2 H), 7.0 (d, 2 H), 4.0 (t, 2H), 3.7 (m, 1H), 2.8 (m, 1 H), 2.4-2.6 (m, 5 H), 2.2 (m, 1 H), 1.8-2.0(m, 2 H), 1.5 (m, 1 H).

EXAMPLE 35N-((3R)-{1-3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-1-methyl-1H-imidazole-4-sulfonamide

[0426]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 1-methyl-1H-imidazole-4-sulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 36N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-thiophenesulfonamide

[0427]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2-thiophenesulfonyl chloride were processed as described in Example20 to provide the title compound.

EXAMPLE 375-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-methyl-1-benzothiophene-2-sulfonamide

[0428]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 5-chloro-3-methyl-1-benzothiophene-2-sulfonyl chloride wereprocessed as described in Example 20 to provide the title compound.

EXAMPLE 38N-((3R)-1-{3-[(4′-cvano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,5-bis(trifluoromethyl)benzenesulfonamide

[0429]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3,5-bis(trifluoromethyl)benzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 39N-(5-{[((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}-4-methyl-1,3-thiazol-2-yl)acetamide

[0430]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2-(acetylamino)-4-methyl-1,3-thiazole-5-sulfonyl chloride wereprocessed as described in Example 20 to provide the title compound.

EXAMPLE 40N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-8-quinolinesulfonamide

[0431]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 8-quinolinesulfonyl chloride were processed as described in Example20 to provide the title compound.

EXAMPLE 414-butoxy-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0432]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-butoxybenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 42 N-((3R)-1-{3-F(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,4-dimethoxybenzenesulfonamide

[0433]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3,4-dimethoxybenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 433-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide

[0434]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3-chloro-4-methylbenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 44N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-phenylethenesulfonamide

[0435]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2-phenylethenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 45N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-(trifluoromethoxy)benzenesulfonamide

[0436]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2-(trifluoromethoxy)benzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 462-cyano-N-((3R)-1-{3-[(4′-cvano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0437]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2-cyanobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 47N-((3R)-1-{3-[(4′-cyanol[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-methylbenzenesulfonamide

[0438]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3-methylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 48N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]proplyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide

[0439]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-(trifluoromethyl)benzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 49N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-fluorobenzenesulfonamide

[0440]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3-fluorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 50N-((3R)-1-{3-[(4′-cyano[1,1-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethoxy)benzenesulfonamide

[0441]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-(trifluoromethoxy)benzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 51N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2,4-difluorobenzenesulfonamide

[0442]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 2,4-difluorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 52N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-7-isoquinolinesulfonamide

[0443]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 7-isoquinolinesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 53N-(2-chloro-4-{((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)aminolsulfonyl}phenyl)acetamide

[0444]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 4-(acetylamino)-3-chlorobenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 543,4-dichloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide

[0445]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand 3,4-dichlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 55 N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0446](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand benzenesulfonyl chloride were processed as described in Example 20to provide the title compound.

EXAMPLE 564-bromo-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0447](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-bromobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 57N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide

[0448](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-fluorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 58

[0449]4-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0450](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-chlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 59N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methoxybenzenesulfonamide

[0451](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-methoxybenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 604-tert-butyl-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0452](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-tert-butylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 61N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide

[0453](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-methylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 62N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-(trifluoromethyl)benzenesulfonamide

[0454](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3-trifluoromethylbenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 63N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2,5-dimethoxybenzenesulfonamide

[0455](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2,5-dimethoxybenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 64N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-methylbenzenesulfonamide

[0456](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2-methylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 653-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide

[0457](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3-chloro-4-fluorobenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 66N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-ethylbenzenesulfonamide

[0458](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-ethylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 67N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-isopropylbenzenesulfonamideEXAMPLE 67A cyclopropyl(4-hydroxyphenyl)methanone

[0459] Sodium hydroxide in water (50% (w/w), 40.4 mL) was treated over aperiod of 15 minutes with para-hydroxy-4-chlorobutyrophenone (25.0 g,137 mmol), followed by additional aqueous sodium hydroxide (25% (w/w),177 mL). Additional para-hydroxy-4-chlorobutyrophenone (25.0 g, 137mmol) was added portionwise to the reaction mixture, followed by solidsodium hydroxide (40.4 g) resulting in the formation of a yellowprecipitate. After refluxing for 60 minutes, water (50 mL) was added andthe resulting mixture was refluxed for another 60 minutes, allowed tocool to ambient temperature, diluted with water (100 mL) and neutralizedwith acetic acid. The precipitate was collected by filtration, washedwith water, air-dried, and triturated at 40° C. with chloroform (1.5 L).The chloroform solution was dried (MgSO₄), filtered, and concentrated.The residue was crystallized from chloroform/hexanes to provide 26.65 g(95%) of the title compound. MS (APCI(−)) m/z 161 (M−H)⁻; ¹H NMR (300MHz, CDCl₃) δ 7.9 (d, 2H), 6.9 (d, 2H), 2.65 (m, 1H), 1.23 (m, 2H), 1.03(m, 2H).

EXAMPLE 67B (4-(3-chloropropoxy)phenyl)(cyclopropyl)methanone

[0460] Cyclopropyl(4-hydroxyphenyl)methanone (10 g, 61.7 mmol), K₂CO₃(12.7 g, 91.9 mmol), and 1-bromo-3-chloropropane (10.74 g, 68.2 mmol) in2-butanone (100 mL) were refluxed for 24 hours, allowed to cool toambient temperature, filtered, and concentrated. The residue was heatedat 40° C. under reduced pressure for three hours to provide the titlecompound of sufficient purity for subsequent use without furtherpurification (13.25 g, 90%).

EXAMPLE 67C(4-{3-[(3R)-3-aminopyrrolidinyl]propoxyl}phenyl)(cyclopropyl)methanone

[0461] (4-(3-Chloropropoxy)phenyl)(cyclopropyl)methanone was processedas described in Examples 9B and 9C to provide the title compound.

EXAMPLE 67DN-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-isopropylbenzenesulfonamide

[0462](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-(2-propyl)benzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

[0463] MS (ESI+) m/z 472 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.0 (d, 2H), 7.7 (d, 2 H), 7.4 (d, 2 H), 7.0 (d, 2 H), 4.1 (t, 2 H), 3.8 (br s, 1H), 3.0 (m, 1 H), 2.85 (m, 1 H), 2.48-2.6 (m, 4 H), 2.2 (m, 1 H),1.8-1.95 (m, 2 H), 1.5 (m, 1 H), 1.1 (d, 6 H), 1.0 (d, 4 H).

EXAMPLE 68N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-fluorobenzenesulfonamide

[0464](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2-fluorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 692-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0465](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2-chlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 703-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0466](4-{(3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3-chlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 713-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0467](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3-cyanobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 72N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-3-fluorobenzenesulfonamide

[0468] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and3-fluorobenzenesulfonyl chloride were processed as described in Example20 to provide the title compound.

EXAMPLE 73N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-(trifluoromethoxy)benzenesulfonamide

[0469] 1-(4-{(3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and4-(trifluoromethoxy)benzenesulfonyl chloride were processed as describedin Example 20 to provide the title compound.

[0470] MS (ESI+) m/z 486 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.0 (d, 2H), 7.7 (d, 2 H), 7.6 (d, 2 H), 7.0 (d, 2 H), 4.1 (t, 2 H), 3.6 (m, 1H), 2.8 (m, 2 H), 2.4-2.5 (m, 2 H), 2.2 (m, 1 H), 1.8-1.9 (m, 4 H), 1.45(m, 1 H), 1.25 (s, 9 H), 1.00 (d, 4 H).

EXAMPLE 74N-{(3R)-1-[3-(4-acetylphenoxy)propyllpyrrolidinyl}-2,4-difluorobenzenesulfonamide

[0471] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and2,4-difluorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 75N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-isoquinolinesulfonamide

[0472] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and5-isoquinolinesulfonyl chloride were processed as described in Example20 to provide the title compound.

Example 76N-{4-[{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}amino)sulfonyl]-2-chlorophenyl}acetamide

[0473] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and4-(acetylamino)-3-chlorobenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 77N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-3,4-dichlorobenzenesulfonamide

[0474] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and3,4-dichlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 78N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1H-pyrrole-2-sulfonamide

[0475] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1H-pyrrole-2-sulfonylchloride were processed as described in Example 20 to provide the titlecompound.

EXAMPLE 79N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}benzenesulfonamide

[0476] 1-(4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)ethanone and4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}benzenesulfonylchloride were processed as described in Example 20 to provide the titlecompound.

EXAMPLE 80N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-1-methyl-1H-imidazole-4-sulfonamide

[0477](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 1-methyl-1H-imidazole-4-sulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 81N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-thiophenesulfonamide

[0478](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2-thiophenesulfonyl chloride were processed as described in Example20 to provide the title compound.

EXAMPLE 825-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-methyl-1-benzothiophene-2-sulfonamide

[0479](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 5-chloro-3-methyl-1-benzothiophene-2-sulfonyl chloride wereprocessed as described in Example 20 to provide the title compound.

EXAMPLE 83N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3,5-bis(trifluoromethyl)benzenesulfonamide

[0480](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3,5-bis(trifluoromethyl)benzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 84N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-8-quinolinesulfonamide

[0481](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 8-quinolinesulfonyl chloride were processed as described in Example20 to provide the title compound.

EXAMPLE 854-butoxy-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0482](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-butoxybenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

[0483] MS (ESI+) m/z 501 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.0 (d, 2H), 7.65 (d, 2 H), 7.6 (d, 1 H), 7.15 (d, 2 H), 7.0 (d, 2 H), 4.1 (m, 4H), 3.6 (m, 1 H), 2.8 (m, 1 H), 2.4-2.7 (m, 4 H), 2.2 (m, 1 H), 1.65-1.8(m, 6 H), 1.4 (m, 3 H), 1.00 (d, 4 H), 0.95 (t, 3 H).

EXAMPLE 86N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3,4-dimethoxybenzenesulfonamide

[0484]((4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3,4-dimethoxybenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 873-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide

[0485](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3-chloro-4-methylbenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 88N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-phenylethenesulfonamide

[0486](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2-phenylethenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 89N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-(trifluoromethoxy)benzenesulfonamide

[0487](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2-(trifluoromethoxy)benzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 902-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0488](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 2-cyanobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 91N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-methylbenzenesulfonamide

[0489](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3-methylbenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 92N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide

[0490](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-trifluoromethylbenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 93N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-fluorobenzenesulfonamide

[0491](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3-fluorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 94N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-(trifluoromethoxy)benzenesulfonamide

[0492](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-(trifluoromethoxy)benzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 95N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-8-isoquinolinesulfonamide

[0493](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 8-isoquinolinesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 96N-(2-chloro-4-{1((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide

[0494](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 4-(acetylamino)-3-chlorobenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 973,4-dichloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0495](4-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}phenyl)(cyclopropyl)methanoneand 3,4-dichlorobenzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 98 tert-butyl1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}-3-pyrrolidinylcarbamate

[0496]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrileand tert-butyl pyrrolidinylcarbamate were processed as described inExamples 9A-9C to provide the title compound.

EXAMPLE 994′-{3-[(3R)-3-aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile

[0497] 4′-Hydroxy[1,1′-biphenyl]-4-carbonitrile was processed asdescribed in Examples 9A-C to provide the title compound.

[0498] MS (APCI+) m/z 322 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.25 (m,1H), 1.80 (m, 1H), 1.99-2.20 (m, 2H), 2.74-3.09 (m, 4H), 3.20 (m, 1H),3.78 (m, 1H), 4.08 (t, 2H, J=6.0 Hz), 4.39-5.03 (m, 2H), 6.97 (d, 2H,J=8.8 Hz), 7.52 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=8.5 Hz), 7.69 (d, 2H,J=8.5 Hz).

EXAMPLE 100 tert-butyl(3S)-1-{2-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]ethyl}pyrrolidinylcarbamate

[0499] 4′-Hydroxy[1,1′-biphenyl]-4-carbonitrile, 1-bromo-2-chloroethaneand tert-butyl (3S)-pyrrolidinylcarbamate were processed as described inExamples 9A and 9B to provide the title compound.

EXAMPLE 1014-methoxy-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0500] (3R)-1-{3-[4-(2-Pyridinyl)phenoxy]propyl}pyrrolidinylamine and4-methoxybenzenesulfonyl chloride were processed as described in Example20 to provide the title compound.

EXAMPLE 1024-isopropyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamideEXAMPLE 102A (3R)-1-{3-[4-(2-Pyridinyl)phenoxy]propyl}pyrrolidinylamine

[0501] 4-(2-Pyridinyl)phenol was processed as described in Examples9A-9C to provide the title compound.

[0502] MS (ESI+) m/z 298 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (m,1H), 7.75 (d, 2H), 7.6 (m, 1H), 7.55 (m, 1H), 7.1 (m, 1 H), 6.9 (d, 2H),4.25 (t, 2H), 3.7 (m, 1H), 2.5-2.3 (m, 5H), 2.10 (m, 1H), 1.8-1.6 (m,2H), 1.4 (m, 2H).

EXAMPLE 102B4-isopropyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0503] (3R)-1-{3-[4-(2-Pyridinyl)phenoxy]propyl}pyrrolidinylamine and4-(2-propyl)benzenesulfonyl chloride were processed as described inExample 20 to provide the title compound.

[0504] MS (ESI+) m/z 480 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.66 (d,1H), 7.95 (m, 2H), 7.85 (d, 1H), 7.70 (m, 3H), 7.37 (d, 1H), 7.20 (m,1H), 6.94 (m, 3H), 4.1 (t, 2H), 3.8 (br s, 1H), 3.0 (m, 1H), 2.85 (m,1H), 2.48-2.6 (m, 4H), 2.2 (m, 1H), 1.8-1.95 (m, 2H), 1.5 (m, 1H), 1.1(d, 6H).

EXAMPLE 1034-cyano-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0505] (3R)-1-{3-[4-(2-Pyridinyl)phenoxy]propyl}pyrrolidinylamine and4-cyanobenzenesulfonyl chloride were processed as described in Example20 to provide the title compound.

EXAMPLE 1043-cyano-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0506] (3R)-1-{3-[4-(2-Pyridinyl)phenoxy]propyl}pyrrolidinylamine and3-cyanobenzenesulfonyl chloride were processed as described in Example20 to provide the title compound.

[0507] MS (ESI+) m/z 463 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.56 (d, 1H), 8.21 (d, 1 H), 8.18 (s, 1 H), 7.88 (d, 2 H), 7.72 (m, 1 H), 7.5 (m,2 H), 7.45 (m, 1 H), 7.0 (m, 1 H), 6.85 (d, 2 H), 4.1 (t, 2 H), 3.6 (m,1H), 2.8 (m, 2 H), 2.4-2.5 (m, 2 H), 2.2 (m, 1 H), 1.8-1.9 (m, 4 H),1.45 (m, 1 H).

EXAMPLE 1051-methyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)-1H-imidazole-4-sulfonamide

[0508] (3R)-1-{3-[4-(2-Pyridinyl)phenoxy]propyl}pyrrolidinylamine and1-methyl-1H-imidazole-4-sulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 1063,4-dimethoxy-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide

[0509] (3R)-1-{3-[4-(2-Pyridinyl)phenoxy]propyl}pyrrolidinylamine and1-methyl-1H-imidazole-4-sulfonyl chloride were processed as described inExample 20 to provide the title compound.

EXAMPLE 107N-(2-chloro-4-{r((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)aminolsulfonyl}phenyl)acetamide

[0510] (3R)-1-{3-[4-(2-Pyridinyl)phenoxy]propyl}pyrrolidinylamine and4-(acetylamino)-3-chlorobenzenesulfonyl chloride were processed asdescribed in Example 20 to provide the title compound.

EXAMPLE 1084′-{3-[(3R)-3-(dimethylamino)pyrrolidinyl]propoxyl}[1,1′-biphenyl]-4-carbonitrile

[0511]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(200 mg, 0.74 mmol), N,N-dimethyl-N-[(3R)-pyrrolidinyl]amine (85 mg,0.74 mmol), 250 mg of potassium carbonate and 300 mg of potassium iodidein 20 mL of 2-butanone were heated at 110° C. for 72 hours. The mixturewas evaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the titlecompound.

[0512] MS (ESI+) m/z 350 (M+H)⁺; ¹³C NMR(500 MHz, CD₃OD) 29.3, 29.6,43.9, 54.2, 54.3, 59.6, 66.5, 67.3, 111.0, 116.2, 119.9, 128.2, 129.4,132.7, 133.7, 146.7, 161.2; ¹H NMR (500 MHz, CD₃OD) 1.74 (m, 1H), 2.0(m, 2H), 2.02 (m, 1H) 2.23 (s, 6H), 2.32 (m, 1H), 2.51 (m, 1H), 2.62 (m,1H), 2.71 (m, 1H), 2.84 (m, 2H), 2.97 (m, 1H), 4.08 (t, J=7 Hz, 2H),7.02 (d, J=11 Hz, 2H), 7.61 (d, J=11 Hz, 2H), 7.74 (s, 4H).

EXAMPLE 109 tert-butyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate

[0513]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(2.31 g, 8.54 mmol), tert-butyl methyl[(3R)-pyrrolidinyl]carbamate (1.71g, 8.54 mmol), potassium carbonate (2.95 g, 21.34 mmol) and potassiumiodide (3.54 g, 21.34 mmol) in 75 mL of 2-butanone were heated at 115°C. for 72 hours. The mixture was evaporated under reduced pressure andthe residue was purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1)to provide the title compound (89% yield).

[0514] MS (APCI+) m/z 436 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.45 (s,9H), 1.8 (m, 2H), 2.1 (m, 2H), 2.4 (m, 2H), 2.7 (m, 2H), 2.85 (s, 3H),4.1 (t, J=7Hz, 2H), 4.25 (m, 1H), 4.75 (m, 1H), 6.98 (d, J=9Hz, 2H), 7.5(d, J=9Hz, 2H), 7.65 (m, 4H).

EXAMPLE 1104-{3-[(3R)-3-(methylamino)pyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile

[0515] The product from Example 109 (3.3 g, 7.58 mmol) indichloromethane (100 mL) was treated with trifluoroacetic acid (6.0 ml)at 0° C. After stirring at ambient temperature for 18 hours, the mixturewas evaporated under reduced pressure. The residue was partitionedbetween saturated aqueous sodium bicarbonate (2×30 mL) anddichloromethane (150 mL). The organic layer was washed with brine (50mL), dried over sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure and the residue purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (95% yield).

[0516] MS (APCI+) m/z 336 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.62 (m,1H), 2.00 (m, 2H), 2.13 (m, 1H), 2.26 (m, 1H), 2.41 (s, 3H), 2.43-2.83(m, 5H), 3.25 (m, 1H), 4.08 (t, 2H, J=6.3 Hz), 6.99 (d, 2H, J=8.9 Hz),7.52 (d, 2H, J=8.8 Hz), 7.66 (dd, 4H, J=16.8, 8.6 Hz).

EXAMPLE 111N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylacetamide

[0517] The product from Example 110 (50 mg, 0.15 mmol), acetic anhydride(0.021 ml, 0.22 mmol), and N,N-diisopropylethylamine (50 μL, 0.30 mmol)in 2 mL of dichloromethane were stirred at 20° C. for 18 hours. Themixture was evaporated under reduced pressure and the residue waspurified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide thetitle compound (60% yield).

[0518] MS (APCI+) m/z 378 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.12 (m,5H), 2.32 (m, 7H), 2.65 (s, 3H), 2.83-3.18 (m, 7H), 3.23-3.79 (m, 9H),3.87-4.20 (m, 7H), 5.38 (m, 1H), 5.64-5.94 (m, 1H), 6.97 (m, 2H), 7.53(d, 2H, J=8.8 Hz), 7.66 (dd, 4H, J=20.2, 8.6 Hz).

EXAMPLE 112N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,3,3-trimethylbutanamide

[0519] The product from Example 110 (50 mg, 0.15 mmol), tert-butylacetylchloride (0.031 ml, 0.22 mmol), and N,N-diisopropylethylamine (50 μL,0.30 mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18hours. The mixture was evaporated under reduced pressure and the residuewas purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to providethe title compound (62% yield).

[0520] MS (APCI+) m/z 434 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.05 (s,9H), 2.11-2.41 (m, 5H), 2.90 (m, 1H), 3.08 (m, 3H), 3.24-3.47 (m, 3H),3.57-3.80 (m, 2H), 3.94 (m, 1H), 4.12 (m, 3H), 6.97 (m, 2H), 7.53 (d,2H, J=8.8 Hz), 7.66 (dd, 4H, J=20.3, 8.8 Hz).

EXAMPLE 113 methyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate

[0521] The product from Example 110 (50 mg, 0.15 mmol), dimethyldicarbonate (0.024 ml, 0.22 mmol), and N,N-diisopropylethylamine (50 μL,0.3 mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18hours. The mixture was evaporated under reduced pressure and the residuewas purified by chromatography (CHCl₃/MeOH/NH₄OH, 9: 1:0.1) to providethe title compound (60% yield).

[0522] MS (APCI+) m/z 394 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 0.89 (m,2H), 1.30-1.52 (m, 2H), 1.44 (s, 3H), 1.77 (m, 1H), 2.15-2.38 (m, 3H),2.65 (s, 3H), 2.91 (m, 3H), 3.18-3.52 (m, 3H), 3.73 (m, 1H), 3.84-4.04(m, 1H), 4.05-4.26 (m, 2H), 6.97 (d, 2H, J=8.5 Hz), 7.53 (d, 2H, J=8.5Hz), 7.66 (dd, 4H, J=20.4, 8.1 Hz).

EXAMPLE 114 tert-pentyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate

[0523] The product from Example 110 (50 mg, 0.15 mmol), di(tert-pentyl)dicarbonate (0.055 ml, 0.22 mmol), and N,N-diisopropylethylamine (50 μL,0.3 mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18hours. The mixture was evaporated under reduced pressure and the residuewas purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to providethe title compound (60% yield).

[0524] MS (APCI+) m/z 450 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 0.90 (s,2H), 1.45 (m, 4H), 1.80 (m, 2H), 2.3 (m, 2H), 2.5 (m, 1H), 2.7 (s, 2H),2.85 (s, 2H), 2.95 (s, 3H), 3.4 (m, 4H), 3.75 (m, 1H), 3.95 (m, 1H),4.15 (t, J=7Hz, 2H), 5.05 (m, 1H), 6.98 (d, J=9Hz, 2H), 7.55 (d, J=9Hz,2H), 7.65 (m, 4H).

EXAMPLE 115N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N,′N′-trimethylurea

[0525] The product from Example 110 (50 mg, 0.15 mmol), dimethylcarbamylchloride (0.021 ml, 0.22 mmol), and N,N-diisopropylethylamine (50 μL,0.30 mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18hours. The mixture was evaporated under reduced pressure and the residuewas purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to providethe title compound (62% yield). ¹H NMR (300 MHz, CDCl₃) δ 2.14-2.40 (m,3H), 2.64 (s, 3H), 2.84 (s, 3H), 2.85 (s, 3H), 3.25-3.46 (m, 3H), 3.52(m, 1H), 3.61-3.81 (m, 1H), 3.98 (m, 1H), 4.13 (m, 2H), 5.73-6.09 (m,1H), 6.98 (m, 2H), 6.98 (m, 2H), 7.53 (d, 2H, J=8.8 Hz), 7.66 (dd, 4H,J=20.1, 8.6 Hz). MS (APCI+) m/z 407 (M+H)⁺.

EXAMPLE 116N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-1-pyrrolidinecarboxamide

[0526] The product from Example 110 (50 mg, 0.15 mmol),1-pyrrolidinecarbonyl chloride (0.030 ml, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0527] MS (APCI+) m/z 433 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.85 (m,3H), 2.17-2.37 (m, 3H), 2.64 (m, 1H), 2.89 (m, 3H), 3.23-3.46 (m, 6H),3.62-3.83 (m, 1H), 3.95 (m, 1H), 4.12 (m, 2H), 6.98 (dd, 2H, J=11.4, 8.6Hz), 7.53 (d, 2H, J=8.8 Hz), 7.66 (dd, 1H, J=20.2, 8.6 Hz).

EXAMPLE 117N′-tert-butyl-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylurea

[0528] The product from Example 110 (50 mg, 0.15 mmol),tert-butylcarbamyl chloride (0.026 ml, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0529] MS (APCI+) m/z 435 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.35 (s,9H), 2.15-2.44 (m, 4H), 2.85 (s, 3H), 3.10-3.43 (m, 3H), 3.57-3.78 (m,1H), 3.81-4.01 (m, 1H), 4.13 (m, 2H), 4.23-4.50 (m, 1H), 5.08-5.37 (m,OH), 6.98 (m, 2H), 7.53 (d, 2H, J=8.8 Hz), 7.66 (dd, 4H, J=20.3, 8.5Hz).

EXAMPLE 118N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-4-morpholinecarboxamide

[0530] The product from Example 110 (50 mg, 0.15 mmol),4-morpholinecarbonyl chloride (0.026 ml, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0531] MS (APCI+) m/z 449 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.14-2.39(m, 3H), 2.89 (d, 3H, J=16.9 Hz), 3.12-3.56 (m, 7H), 3.61-3.82 (m, 5H),3.87-4.22 (m, 3H), 4.42-4.65 (m, 1H), 4.70-5.24 (m, 2H), 6.97 (m, 2H),7.53 (d, 2H, J=8.5 Hz), 7.66 (dd, 4H, J=20.3, 8.4 Hz).

EXAMPLE 119N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluoro-N-methylbenzamide

[0532] The product from Example 110 (50 mg, 0.15 mmol), 4-fluorobenzoylchloride (0.026 ml, 0.22 mmol), and N,N-diisopropylethylamine (50 μL,0.30 mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18hours. The mixture was evaporated under reduced pressure and the residuewas purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to providethe title compound (62% yield).

[0533] MS (APCI+) m/z 458 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.22-2.58(m, 3H), 2.64 (s, 3H), 2.93-3.19 (m, 3H), 3.27-3.94 (m, 5H), 3.96-4.22(m, 3H), 4.23-4.58 (m, 1H), 6.98 (d, 2H, J=8.4 Hz), 7.13 (t, 2H, J=8.5Hz), 7.44 (dd, 2H, J=8.8, 5.5 Hz), 7.53 (d, 2H, J=8.9 Hz), 7.66 (dd, 4H,J=20.7, 8.8 Hz).

EXAMPLE 1204-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylbenzamide

[0534] The product from Example 110 (50 mg, 0.15 mmol), 4-cyanobenzoylchloride (37 mg, 0.22 mmol), and N,N-diisopropylethylamine (50 μL, 0.30mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18 hours.The mixture was evaporated under reduced pressure and the residue waspurified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide thetitle compound (62% yield).

[0535] MS (APCI+) m/z 465 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.18-2.56(m, 4H), 2.63 (s, 3H), 2.89-3.17 (m, 4H), 3.29-3.60 (m, 4H), 3.72-3.96(m, 1H), 4.03-4.24 (m, 3H), 6.97 (d, 2H, J=8.8 Hz), 7.53 (d, 4H, J=7.1Hz), 7.66 (dd, 4H, J=20.9, 8.2 Hz), 7.75 (d, 2H, J=8.2 Hz).

EXAMPLE 121N-((3R)-1-{3-[(4′-cyanor[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylnicotinamide

[0536] The product from Example 110 (50 mg, 0.15 mmol), nicotinoylchloride (40 mg, 0.22 mmol), and N,N-diisopropylethylamine (50 μL, 0.30mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18 hours.The mixture was evaporated under reduced pressure and the residue waspurified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide thetitle compound (62% yield).

[0537] MS (APCI+) m/z 441 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.20-2.61(m, 3H), 2.66 (s, 2H), 2.91-3.24 (m, 3H), 3.24-3.76 (m, 4H), 3.77-3.97(m, 1H), 3.99-4.27 (m, 3H), 6.98 (d, 2H, J=8.5 Hz), 7.53 (d, 2H, J=8.8Hz), 7.66 (dd, 4H, J=20.1, 8.2 Hz), 7.86-8.07 (m, 1H), 8.08-8.50 (m,1H), 8.78 (d, 2H, J=14.6 Hz).

EXAMPLE 122 N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propylpyrrolidinyl)-N-methyl-2-furamide

[0538] The product from Example 110 (50 mg, 0.15 mmol), 2-furoylchloride (0.022 ml, 0.22 mmol), and N,N-diisopropylethylamine (50 μL,0.30 mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18hours. The mixture was evaporated under reduced pressure and the residuewas purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to providethe title compound (62% yield).

[0539] MS (APCI+) m/z 430 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.19-2.60(m, 4H), 2.64 (s, 3H), 3.19-3.61 (m, 6H), 3.62-3.88 (m, 2H), 3.90-4.21(m, 4H), 6.53 (dd, 1H, J=3.4, 1.7 Hz), 6.98 (d, 2H, J=8.1 Hz), 7.06 (m,1H), 7.53 (d, 2H, J=8.8 Hz), 7.67 (dd, 4H, J=20.0, 8.8 Hz).

EXAMPLE 123N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide

[0540] The product from Example 110 (50 mg, 0.15 mmol),2-(3-pyridinyl)-1,3-thiazole-4-carbonyl chloride (46 mg, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.3 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0541] MS (APCI+) m/z 524 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.20 (m,2H), 2.35 (m, 4H), 2.65 (s, 3H), 3.10 (m, 2H), 3.40 (m, 4H), 4.15 (m,2H), 6.98 (d, J=9Hz, 2H), 7.50 (d, J=9Hz, 2H), 7.65 (m, 4H), 8.05 (s,1H), 8.40 (m, 1H), 8.70 (m, 1H), 9.20 (m, 1H).

EXAMPLE 124N-[(3R)-1-[3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl]pyrrolidinyl]-N,N,N-trimethyl-sulfamide

[0542] The product from Example 110 (50 mg, 0.15 mmol),dimethylsulfamoyl chloride (0.024 ml, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0543] MS (APCI+) m/z 443 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.15-2.56(m, 4H), 2.65 (s, 3H), 2.71-2.92 (m, 2H), 2.83 (s, 6H), 2.97 (m, 1H),3.18 (m, 1H), 3.36 (m, 2H), 3.85 (m, 1H), 4.12 (m, 2H), 6.97 (d, 2H,J=8.9 Hz), 7.53 (d, 2H, J=8.8 Hz), 7.66 (dd, 4H, J=20.3, 8.4 Hz).

EXAMPLE 125N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-fluoro-N-methylbenzenesulfonamide

[0544] The product from Example 110 (50 mg, 0.15 mmol),3-fluorobenzenesulfonyl chloride (0.039 ml, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0545] MS (APCI+) m/z 494 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.96-2.43(m, 3H), 2.64 (s, 2H), 2.73-2.94 (m, 3H), 3.07 (m, 1H), 3.21-3.43 (m,2H), 4.10 (m, 2H), 6.95 (d, 2H, J=8.8 Hz), 7.34 (m, 1H), 7.53 (d, 2H,J=8.8 Hz), 7.58 (m, 1H), 7.66 (dd, 4H, J=21.2, 8.3 Hz).

EXAMPLE 1264-cyano-N-((3R)-1-≡3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylbenzenesulfonamide

[0546] The product from Example 110 (50 mg, 0.15 mmol),4-cyanobenzenesulfonyl chloride (45 mg, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0547] MS (APCI+) m/z 501 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.30 (m,2H), 2.65 (s, 3H), 2.77-3.01 (m, 2H), 3.09 (m, OH), 3.23-3.43 (m, 2H),4.11 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=8.9 Hz), 7.67 (dd,4H, J=21.2, 8.3 Hz), 7.89 (dd, 4H, J=23.9, 8.3 Hz).

EXAMPLE 127N-((3R)-1-{3-[(4′-cyano[1,1′-bipheny]-1-4-yl)oxy]propyl}pyrrolidinyl)-4-isopropyl-N-methylbenzenesulfonamide

[0548] The product from Example 110 (50 mg, 0.15 mmol),4-(2-propyl)benzenesulfonyl chloride (0.044 ml, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0549] MS (APCI+) m/z 518 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.27 (d, 6H,J=6.7 Hz), 2.11-2.40 (m, 3H), 2.64 (s, 3H), 2.79 (m, 3H), 2.84-3.14 (m,2H), 3.20-3.43 (m, 2H), 4.10 (m, 2H), 6.95 (d, 2H, J=8.8 Hz), 7.38 (d,2H, J=8.2 Hz), 7.52 (d, 2H, J=8.5 Hz), 7.66 (dd, 4H, J=21.4, 8.5 Hz),7.70 (d, 2H, J=8.2 Hz).

EXAMPLE 128N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-4-(methylsulfonyl)benzenesulfonamide

[0550] The product from Example 110 (50 mg, 0.15 mmol),4-(methylsulfonyl)benzenesulfonyl chloride (57 mg, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.3 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (68% yield).

[0551] MS (APCI+) m/z 554 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.30 (m,4H), 2.60 (s, 3H), 2.90 (s, 2H), 3.10 (s, 3H), 3.30 (m, 2H), 4.10 (t,J=7Hz, 2H), 4.95 (m, 1H), 6.95 (d, J=9Hz, 2H), 7.50 (d, J=9Hz, 2H), 7.65(m, 4H), 8.00 (d, J=9Hz, 2H), 8.15 (d, J=9Hz, 2H).

EXAMPLE 129N-((3R)-1-{3-[(4′-cvano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluoro-N-(4-fluorobenzoyl)benzamide

[0552]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 4-fluorobenzoyl chloride (0.028 ml, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (20% yield).

[0553] MS (APCI+) m/z 436 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.24-2.56(m, 4H), 2.56-2.84 (m, 1H), 3.11-3.45 (m, 1H), 3.45-3.78 (m, 4H), 3.93(m, 1H), 4.12 (m, 2H), 4.27 (m, 1H), 5.35-5.62 (m, 1H), 6.82-7.04 (m,6H), 7.44 (m, 4H), 7.52 (d, 2H, J=8.8 Hz), 7.65 (dd, 4H, J=20.0, 8.2Hz).

EXAMPLE 130N-((3R)-1-{3-[(4′-cvano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)acetamide

[0554]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), acetyl chloride (22.0 μl, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (70% yield).

[0555] MS (APCI+) m/z 364 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.0 (m, 3H),2.2-2.6 (m, 4H), 2.9-3.2 (m, 2H), 3.35 (m, 2H), 3.75 (m, 1H), 4.0 (m,1H), 4.15 (m, 2H), 4.9 (m, 1H), 6.95 (d, J=9Hz, 2H), 7.50 (d, J=9Hz,2H), 7.65 (m, 4H), 8.3 (m, 2H).

EXAMPLE 131N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,3-dimethylbutanamide

[0556]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), tert-butylacetyl chloride (0.033 ml, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (52% yield).

[0557] MS (APCI+) m/z 420 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.02 (s,9H), 2.10 (s, 2H), 2.21 (m, 1H), 2.35 (m, 2H), 2.42-2.81 (m, 6H),2.83-3.17 (m, 2H), 3.35 (m, 2H), 3.72 (m, 1H), 3.97 (m, 1H), 4.13 (m,2H), 4.92 (m, 1H), 6.97 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=8.5 Hz), 7.67(dd, 4H, J=21.8, 8.3 Hz).

EXAMPLE 132 allyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate

[0558]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), allyl chloroformate (0.039 ml, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (51% yield).

[0559] MS (APCI+) m/z 406 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.17-2.41(m, 4H), 2.41-2.64 (m, 6H), 2.91 (m, 1H), 3.10 (m, 1H), 3.23-3.46 (m,2H), 3.81 (m, 2H), 4.00 (m, 1H), 4.14 (m, 2H), 4.56 (m, 2H), 4.68 (m,1H), 5.20 (dd, 1H, J=10.3, 0.8 Hz), 5.30 (dd, 1H, J=17.3, 1.4 Hz), 5.90(ddd, 1H, J=22.8, 10.7, 5.7 Hz), 6.80 (m, 1H), 6.97 (d, 2H, J=8.8 Hz),7.53 (d, 2H, J=8.4 Hz), 7.67 (dd, 4H, J=21.6, 8.7 Hz).

EXAMPLE 133 methyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate

[0560]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), methyl chloroformate (0.025 ml, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (51% yield).

[0561] MS (APCI+) m/z 380 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.05 (m,6H), 2.29 (m, 3H), 2.53 (m, 1H), 3.08 (m, 1H), 3.33 (m, 2H), 3.67 (s,3H), 3.77 (m, 1H), 3.98 (m, 1H), 4.14 (t, 2H, J=5.6 Hz), 4.67 (m, 1H),6.96 (d, 2H, J=8.8 Hz), 7.53 (d, 2H, J=9.2 Hz), 7.67 (dd, 4H, J=21.6,8.6 Hz).

EXAMPLE 134 tert-pentyl(3R)-1-{3-[(4-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate

[0562]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 1,1-dimethylpropyl chloroformate (57.1 μL, 0.23mmol), and N,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL ofdichloromethane were stirred at 20° C. for 18 hours. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound(72% yield).

[0563] MS (APCI+) m/z 436 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 0.90 (t,J=7Hz, 3H), 1.4 (s, 6H), 1.75 (m, 2H), 2.2 (m, 1H), 2.35 (m, 2H), 2.5(m, 1H), 2.9 (m, 4H), 3.35 (m, 2H), 3.7 (m, 1H), 4.0 (m, 1H), 4.15 (m,2H), 6.95 (d, J=9Hz, 2H), 7.50 (d, J=9Hz, 2H), 7.65 (m, 4H).

EXAMPLE 135N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N-dimethylurea

[0564]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), dimethylcarbamyl chloride (0.021 ml, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (65% yield).

[0565] MS (APCI+) m/z 393 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.20-2.42(m, 4H), 2.48-2.77 (m, 6H), 2.90 (m, 1H), 2.93 (s, 6H), 3.07 (m, 1H),3.34 (m, 2H), 3.76 (m, 1H), 3.96 (m, 1H), 4.14 (t, 2H, J=5.4 Hz), 4.86(m, 1H), 6.71 (m, 1H), 6.97 (d, 2H, J=8.8 Hz), 7.53 (d, 2H, J=8.8 Hz),7.67 (dd, 4H, J=21.8, 8.7 Hz).

Example 136N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-1-pyrrolidinecarboxamide

[0566]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 1-pyrrolidinecarbonyl chloride (0.031 ml, 0.23mmol), and N,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL ofdichloromethane were stirred at 20° C. for 18 hours. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound(68% yield).

[0567] MS (APCI+) m/z 419 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.90 (m,4H), 2.21-2.43 (m, 3H), 2.59 (m, 1H), 2.83-3.50 (m, 12H), 3.77 (m, 1H),3.97 (m, 1H), 4.15 (t, 2H, J=4.8 Hz), 4.89 (m, 1H), 6.59 (m, 1H), 6.97(d, 2H, J=8.4 Hz), 7.53 (d, 2H, J=8.5 Hz), 7.67 (dd, 4H, J=21.7, 8.5Hz).

EXAMPLE 137N-(tert-butyl)-N′-((3R)-1-{3-[(4′-cyanol[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)urea

[0568]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), tert-butylcarbamyl chloride (0.027 ml, 0.23 mmol),and N,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL ofdichloromethane were stirred at 20° C. for 18 hours. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound(65% yield).

[0569] MS (APCI+) m/z 421 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.31 (s,9H), 2.16 (m, 1H), 2.35 (m, 2H), 2.50 (m, 1H), 2.61-3.08 (m, 4H), 3.33(m, 2H), 3.68 (m, 1H), 3.94 (m, 1H), 4.15 (t, 2H, J=5.6 Hz), 4.74 (m,1H), 6.97 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=9.2 Hz), 7.67 (dd, 4H,J=21.7, 8.8 Hz).

[0570] EXAMPLE 138

N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-morpholinecarboxamide

[0571]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 4-morpholinecarbonyl chloride (0.027 ml, 0.23 mmol),and N,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL ofdichloromethane were stirred at 20° C. for 18 hours. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound(52% yield).

[0572] MS (APCI+) m/z 435 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.24 (m,1H), 2.36 (m, 2H), 2.60 (m, 1H), 2.70-3.01 (m, 4H), 3.10 (m, 1H), 3.33(m, 2H), 3.43 (t, 4H, J=4.6 Hz), 3.67 (t, 4H, J=4.4 Hz), 3.77 (m, 1H),3.97 (m, 1H), 4.15 (t, 2H, J=5.1 Hz), 4.88 (m, 1H), 6.97 (d, 2H, J=8.9Hz), 7.54 (d, 2H, J=8.5 Hz), 7.67 (dd, 4H, J=22.1, 8.5 Hz).

EXAMPLE 139N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzamide

[0573]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 4-fluorobenzoyl chloride (0.027 ml, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (58% yield).

[0574] MS (APCI+) m/z 444 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.36 (m,3H), 2.58-2.88 (m, 3H), 2.99 (m, 1H), 3.18 (m, 1H), 3.29-3.50 (m, 2H),3.90 (m, 1H), 4.03 (m, 1H), 4.16 (t, 2H, J=4.8 Hz), 5.16 (m, 1H), 6.96(d, 2H, J=8.8 Hz), 7.11 (t, 2H, J=8.7 Hz), 7.51 (d, 2H, J=8.8 Hz), 7.66(dd, 4H, J=24.3, 8.7 Hz), 7.66 (dd, 2H), 8.69 (d, 1H, J=7.5 Hz).

EXAMPLE 1404-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzamide

[0575]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 4-cyanobenzoyl chloride (38.6 mg, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62% yield).

[0576] MS (APCI+) m/z 451 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.22-2.47(m, 6H), 2.69 (m, 1H), 3.01 (m, 1H), 3.19 (m, 1H), 3.41 (m, 2H), 3.91(m, 1H), 4.05 (m, 1H), 4.17 (t, 2H, J=5.1 Hz), 5.18 (m, 1H), 6.96 (d,2H, J=8.5 Hz), 7.52 (d, 2H, J=8.5 Hz), 7.66 (dd, 4H, J=24.7, 8.5 Hz),7.73 (d, 2H, J=8.8 Hz), 8.10 (d, 2H, J=8.1 Hz), 9.05 (m, 1H).

EXAMPLE 141N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)nicotinamide

[0577]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), nicotinoyl chloride (41.5 mg, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (65% yield).

[0578] MS (APCI+) m/z 427 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.39 (m,3H), 2.71 (m, 1H), 3.07 (m, 1H), 3.24 (m, 1H), 3.43 (m, 2H), 3.93 (m,1H), 4.05 (m, 1H), 4.17 (t, 2H, J=5.1 Hz), 6.96 (d, 2H, J=9.2 Hz), 7.53(d, 2H, J=8.8 Hz), 7.66 (dd, 4H, J=24.1, 8.5 Hz), 7.77 (dd, 1H, J=8.2,5.4 Hz), 8.81 (dt, 1H, J=8.1, 1.7 Hz), 8.88 (dd, 1H, J=5.5, 1.4 Hz),9.36 (d, 1H, J=1.7 Hz), 9.60 (d, 1H, J=8.2 Hz).

EXAMPLE 142N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-furamide

[0579]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 2-furoyl chloride (0.023 ml, 0.22 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (68% yield).

[0580] MS (APCI+) m/z 416 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.29-2.49(m, 4H), 2.57-2.79 (m, 2H), 2.79-3.05 (m, 5H), 3.07-3.28 (m, 1H), 3.37(m, 1H), 3.46-3.73 (m, 4H), 3.89 (m, 1H), 4.17 (m, 4H), 5.35 (m, 1H),6.45 (m, 2H), 6.98 (m, 2H), 7.11 (d, 2H, J=3.4 Hz), 7.42 (m, 2H), 7.53(d, 2H, J=8.8 Hz), 7.67 (dd, 4H, J=20.2, 8.3 Hz).

EXAMPLE 143N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide

[0581]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 2-(3-pyridinyl)-1,3-thiazole-4-carbonyl chloride(48.1 mg, 0.23 mmol), and N,N-diisopropylethylamine (50 μL, 0.30 mmol)in 2 mL of dichloromethane were stirred at 20° C. for 18 hours. Themixture was evaporated under reduced pressure and the residue waspurified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide thetitle compound (72% yield).

[0582] MS (APCI+) m/z 510 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.4 (m, 2H),2.65 (m, 1H), 3.0 (m, 1H), 3.2-3.6 (m, 2H), 4.0 (m, 1H), 4.20 (m, 2H),4.95 (m, 4H), 5.2 (m, 1H), 6.95 (d, J=9Hz, 2H), 7.50 (d, J=9Hz, 2H), ),7.55 (m, 1H), 7.65 (m, 4H), 7.85 (m, 1H), 8.25 (s, 1H), 8.8 (m, 1H), 9.3(m, 1H).

EXAMPLE 144N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-propanesulfonamide

[0583]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 2-propanesulfonyl chloride (26.2 μL, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (70% yield).

[0584] MS (APCI+) m/z 428 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.4 (d,J=7Hz, 6H), 2.4 (m, 2H), 2.6 (m, 2H), 2.9 (m, 2H), 3.1 (m, 2H), 3.4 (m,2H), 3.95 (m, 2H), 4.15 (m, 2H), 4.4 (m, 1H), 6.95 (d, J=9Hz, 2H), 7.50(d, J=9Hz, 2H), ), 7.65 (m, 4H).

EXAMPLE 145N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N-dimethylsulfamide

[0585]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), dimethylsulfamoyl chloride (0.025 ml, 0.23 mmol),and N,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL ofdichloromethane were stirred at 20° C. for 18 hours. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound(65% yield).

[0586] MS (APCI+) m/z 429 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.14-2.42(m, 8H), 2.57 (m, 1H), 2.82 (s, 6H), 3.07 (m, 1H), 3.34 (m, 2H), 3.97(m, 2H), 4.14 (t, 2H, J=5.6 Hz), 4.36 (m, 1H), 6.97 (d, 2H, J=8.8 Hz),7.54 (d, 2H, J=8.8 Hz), 7.67 (dd, 4H, J=21.6, 8.6 Hz).

EXAMPLE 146N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(methylsulfonyl)benzenesulfonamide

[0587]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 4-(methylsulfonyl)benzenesulfonyl chloride (59.4 mg,0.23 mmol), and N,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL ofdichloromethane were stirred at 20° C. for 18 hours. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound(75% yield).

[0588] MS (APCI+) m/z 540 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.13 (m,2H), 2.23-2.51 (m, 8H), 2.85 (m, 1H), 3.00 (m, 1H), 3.10 (s, 3H), 3.30(m, 2H), 3.72 (m, 1H), 3.88 (m, 1H), 4.12 (t, 2H, J=5.4 Hz), 4.37 (m,1H), 6.95 (d, 2H, J=8.8 Hz), 7.53 (d, 2H, J=8.9 Hz), 7.66 (dd, 4H,J=22.1, 8.5 Hz), 8.11 (d, 4H, J=3.1 Hz).

EXAMPLE 147N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(3,3-dimethylbutanoyl)-3,3-dimethylbutanamide

[0589]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), tert-butylacetyl chloride (0.032 ml, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (25% yield).

[0590] MS (APCI+) m/z 518 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.06 (s,18H), 2.19-2.42 (m, 3H), 2.55 (s, 2H), 2.58 (s, 2H), 3.04-3.53 (m, 8H),3.60 (m, 1H), 3.67-4.06 (m, 2H), 4.13 (t, 2H, J=5.4 Hz), 4.92 (m, 1H),6.97 (d, 2H, J=8.9 Hz), 7.53 (d, 2H, J=8.8 Hz), 7.67 (dd, 4H, J=20.9,8.6 Hz).

EXAMPLE 148N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N′-(dimethylaminocarbonyl)-N,N-dimethylurea

[0591]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), dimethylcarbamyl chloride (0.021 ml, 0.23 mmol), andN,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL of dichloromethanewere stirred at 20° C. for 18 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (30% yield).

[0592] MS (APCI+) m/z 464 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.86-2.18(m, 3H), 2.36 (m, 1H), 2.82 (s, 6H), 2.87-3.07 (m, 10H), 3.10 (s, 3H),3.25 (s, 3H), 3.30-3.52 (m, 4H), 4.01 (t, 2H, J=5.6 Hz), 4.15 (m, 1H),4.34 (m, 1H), 4.50 (m, 1H), 4.87 (m, 1H), 6.97 (d, 2H, J=8.8 Hz), 7.53(d, 2H, J=9.1 Hz), 7.67 (dd, 4H, J=17.8, 8.7 Hz).

EXAMPLE 149 N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(1-pyrrolidinylcarbonyl)-1-pyrrolidinecarboxamide

[0593]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 1-pyrrolidinecarbonyl chloride (0.031 ml, 0.23mmol), and N,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL ofdichloromethane were stirred at 20° C. for 18 hours. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound(25% yield).

[0594] MS (APCI+) m/z 516 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.78 (m,2H), 1.87-2.20 (m, 5H), 2.21-2.47 (m, 1H), 3.17-3.59 (m, 7H), 3.68 (m,2H), 3.77-4.25 (m, 6H), 4.35 (m, 1H), 4.52 (m, 1H), 4.77-5.00 (m, 1H),6.97 (d, 2H, J=8.8 Hz), 7.53 (d, 2H, J=8.4 Hz), 7.67 (dd, 4H, J=18.3,8.5 Hz).

EXAMPLE 150N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(4-morpholinylcarbonyl)-4-morpholinecarboxamide

[0595]4′-{(3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(50 mg, 0.15 mmol), 4-morpholinecarbonyl chloride (0.027 ml, 0.23 mmol),and N,N-diisopropylethylamine (50 μL, 0.30 mmol) in 2 mL ofdichloromethane were stirred at 20° C. for 18 hours. The mixture wasevaporated under reduced pressure and the residue was purified bychromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound(75% yield). 1H NMR (300 MHz, CDCl₃) δ 2.09 (m, 2H), 2.34 (m, 1H), 3.22(m, 3H), 3.44 (m, 6H), 3.57 (m, 4H), 3.68 (m, 7H), 3.80 (m, 5H), 4.02(t, 2H, J=5.4 Hz), 4.13 (m, 1H), 4.36 (m, 1H), 4.53 (m, 1H), 4.90 (m,1H), 6.96 (d, 2H, J=8.5 Hz), 7.53 (d, 2H, J=8.8 Hz), 7.67 (dd, 4H,J=19.3, 8.8 Hz). MS (APCI+) m/z 548 (M+H)⁺.

EXAMPLE 151cyclopropyl{4-[3-(3-hydroxy-1-pyrrolidinyl)propoxy]phenyl}methanoneEXAMPLE 151A cyclopropyl(4-hydroxyphenyl)methanone

[0596] Sodium hydroxide in water (50% (w/w), 40.4 mL) was treated over aperiod of 15 minutes with para-hydroxy-4-chlorobutyrophenone (25.0 g,137 mmol), followed by additional aqueous sodium hydroxide (25% (w/w),177 mL). Additional para-hydroxy-4-chlorobutyrophenone (25.0 g, 137mmol) was added portionwise to the reaction mixture, followed by solidsodium hydroxide (40.4 g). A yellow precipitate formed. After refluxingfor 60 minutes, water (50 mL) was added and the resulting mixture wasrefluxed for another 60 minutes, cooled to room temperature, dilutedwith water (100 mL) and neutralized with acetic acid. The precipitatewas collected by filtration, washed with water, air-dried, andtriturated at 40° C. with chloroform (1.5 L). The chloroform solutionwas dried (MgSO₄), filtered, and concentrated. The concentrate wasrecrystallized from chloroform/hexanes to afford 26.65 g (95%) of thedesired product.

[0597] MS (APCI−) m/z 161 (M−H)⁻; ¹H NMR (300 MHz, CDCl₃) δ 7.9 (d, 2H),6.9 (d, 2H), 2.65 (m, 1H), 1.23 (m, 2H), 1.03 (m, 2H).

EXAMPLE 151B (4-(3-chloropropoxy)phenyl)(cyclopropyl)methanone

[0598] The product from Example 151A (10 g, 61.7 mmol), K₂CO₃ (12.7 g,91.9 mmol), and 1-bromo-3-chloropropane (10.74 g, 68.2 mmol) in2-butanone (100 mL) was refluxed for 24 hours, cooled to ambienttemperature, filtered, and concentrated. The filtrate was heated at 40°C. under reduced pressure for 3 hours to provide the title compound(13.256 g, 90% yield) of sufficient purity for subsequent use withoutfurther purification.

EXAMPLE 151C cyclopropyl{4-[3-(3-hydroxy-1-pyrrolidinyl)propoxy]phenyl}methanone

[0599] The product from Example 151B (200 mg, 0.83 mmol),3-hydroxypyrrolidine (72 mg, 0.83 mmol), potassium carbonate (121 mg)and potassium iodide (146 mg) in 10 mL of 2-butanone were heated at 110°C. for 72 hours. The mixture was evaporated under reduced pressure andthe residue was purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1)to provide the title compound (68 % yield).

[0600] MS (ESI+) m/z 290 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 0.93 (m, 2H),1.20 (m, 2H), 4.18 (t, J=5 Hz, 2H), 4.42 (s, 1H), 6.90 (d, J=7 Hz, 2H),8.00 (d, J=7 Hz, 2H).

EXAMPLE 152cyclopropyl(4-{3-[(3R)-3-hydroxypyrrolidinyl]propoxy}phenyl)methanone

[0601] (4-(3-Chloropropoxy)phenyl)(cyclopropyl)methanone (150 mg, 0.63mmol), 3-(3R)-hydroxypyrrolidine (55 mg, 0.63 mmol), potassium carbonate(152 mg) and potassium iodide (183 mg) in 25 mL of 2-butanone wereheated at 110° C. for 72 hours. The mixture was evaporated under reducedpressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (62 % yield).

[0602] MS (ESI+) m/z 290 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 0.95 (m, 2H),1.21 (m, 2H), 4.13 (t, J=5 Hz, 2H), 4.40 (s, 1H), 6.95 (d, J=7 Hz, 2H),8.00 (d, J=7 Hz, 2H).

EXAMPLE 1533-[(3R)-{3-hydroxypyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile

[0603]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(200 mg, 0.74 mmol), (3R)-3-pyrrolidinol (70 mg, 0.81 mmol), potassiumcarbonate (152 mg) and potassium iodide (183 mg) in 25 mL of 2-butanonewere heated at 110° C. for 72 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (69 % yield).

[0604] MS (ESI+) m/z 323 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 3.0 (m, 1H),4.13 (t, J=5 Hz, 2H), 4.40 (s, 1H), 7.0 (d, J=7 Hz, 2H), 7.55 (d, J=7Hz, 2H), 7.65 (m, 4H).

EXAMPLE 1544′-[3-{3-oxo-1-pyrrolidinyl)propoxyl][1,1′-biphenyl]-4-carbonitrile

[0605] Oxalyl chloride (0.195 mmol) in dry CH₂Cl₂ (5 mL) under anatmosphere of nitrogen at −78° C. was treated with DMSO (0.39 mmol).After 15 minutes of stirring, the product from Example 153 was added andthe mixture was stirred for another 15 minutes. Triethylamine (0.45mmol) was added and the mixture was gradually allowed to warm to 0° C.The solution was partitioned between water (50 mL) and dichloromethane(50 mL). The organic layer was washed with brine (50 mL), dried oversodium sulfate and filtered. The filtrate was evaporated under reducedpressure and the residue purified by chromatography (CHCl₃:MeOH:NH₄OH,9:1:0.1) to provide the title compound (60% yield).

[0606] MS (ESI+) m/z 321 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.15 (t, J=5Hz, 2H), 7.00 (d, J=7 Hz, 2H), 7.57 (d, J=7 Hz, 2H), 7.63 (m, 4H).

EXAMPLE 155 4′-{3-[(3S)-3-hydroxypyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile

[0607]4′-3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(180 mg, 0.65 mmol), (3S)-3-pyrrolidinol (57 mg, 0.65 mmol), potassiumcarbonate (140 mg) and potassium iodide (180 mg) in 20 mL of 2-butanonewere heated at 110° C. for 72 hours. The mixture was evaporated underreduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (61 % yield).

[0608] MS (ESI+) m/z 323 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.02 (m, 2H),2.25 (m, 3H), 4.15 (t, J=5 Hz, 2H), 6.99 (d, J=7 Hz, 2H), 7.55 (d, J=7Hz, 2H), 7.65 (m, 4H).

EXAMPLE 1564-[3-3-hydroxy-3-methyl-1-pyrrolidinyl)propoxy][1,1′-biphenyl]-4-carbonitrile

[0609] The product from Example 154 (130 mg, 0.41 mmol) in dry THF (6mL) under an atmosphere of nitrogen at 0° C. was treated with a 3.0Msolution of methylmagnesium bromide (0.82 mmol). After warming toambient temperature and stirring for 2 hours, the mixture was quenchedwith 3 mL of cold saturated ammonium chloride solution and then thesolution was partitioned between water (50 mL) and dichloromethane (50mL). The organic layer was washed with brine (50 mL), dried over sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureand the residue purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1)to provide the title compound (55% yield).

[0610] MS (ESI+) m/z 337 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.22 (s, 3H),1.93 (m, 2H), 2.1 (m, 2H), 2.82 (m, 2H), 2.92 (d, J=8 Hz, 1H), 3.23 (m,1H), 4.05 (t, J=5 Hz, 2H), 7.00 (d, J=7 Hz, 2H), 7.57 (d, J=7 Hz, 2H),7.63 (m, 4H).

EXAMPLE 1574-[3-(3-hydroxy-3-isopropyl-1-pyrrolidinyl)propoxy][1,1′-biphenyl]-4-carbonitrile

[0611] The product from Example 154 (147 mg, 0.46 mmol) in dry THF (10mL) under an atmosphere of nitrogen at 0° C. was treated with a 2.0Msolution of isopropylmagnesium chloride (0.92 mmol). After warming toambient temperature and stirring for 1 hour, the mixture was quenchedwith 5 mL of cold saturated ammonium chloride solution and then thesolution was partitioned between water (50 mL) and dichloromethane (50mL). The organic layer was washed with brine (50 mL), dried over sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureand the residue purified by chromatography (CHCl₃:MeOH:NH₄OH, 9:1:0.1)to provide the title compound (75% yield).

[0612] MS (ESI+) m/z 365 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 4.25 (t, J=5Hz, 2H), 6.98 (d, J=7 Hz, 2H), 7.55 (d, J=7 Hz, 2H), 7.62 (m, 4H).

EXAMPLE 1584′-{3-[(3R)-3-hydroxy-3-methylpyrrolidiny]lpropoxy}[1,1′-biphenyl]-4-carbonitrile

[0613]4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile(177 mg, 0.65 mmol), (3R)-3-methyl-3-pyrrolidinol (75 mg, 0.74 mmol),potassium carbonate (153 mg) and potassium iodide (184 mg) in 10 mL ofDMF were heated at 110° C. for 10 hours. The mixture was evaporatedunder reduced pressure and the residue was purified by chromatography(CHCl₃:MeOH:NH₄OH, 9:1:0.1) to provide the title compound (40 % yield).

[0614] MS (ESI+) m/z 337 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.2 (s, 3H),4.15 (t, J=5 Hz, 2H), 6.98 (d, J=7 Hz, 2H), 7.55 (d, J=7 Hz, 2H), 7.69(m, 4H).

EXAMPLE 159N,N-dimethyl-N-[(3R)-1-(3-{4′-(1,1-pyrrolidinylcarbonyl)[1,1′-biphenyl]-4-ylloxy}propyl)pyrrolidinyl]amine

[0615] 1-{[4′-(3-Chloropropoxy)[1,1′-biphenyl]-4-yl]carbonyl}pyrrolidine(200 mg, 0.74 mmol), N,N-dimethyl-N-[(3R)-pyrrolidinyl]amine (70 mg,0.81 mmol), potassium carbonate (152 mg) and potassium iodide (183 mg)in 25 mL of 2-butanone were heated at 110° C. for 72 hours. The mixturewas evaporated under reduced pressure and the residue was purified byHPLC chromatography (0 to 95% CH₃CN in H₂O with 0.1% TFA, 10 minutelinear gradient) to provide the title compound in 79% yield. ¹HNMR (500MHz, CDCl₃) δ 1.89 (m, 2H), 1.97 (m, 2H), 2.26 (m, 2H), 2.57 (m, 3H),2.86 (s, 6H), 3.40 (m, 3H), 3.49 (t, 2H, J=6.7 Hz), 3.67 (t, 2H, J=6.8Hz), 3.74 (m, 1H), 3.84 (dd, 1H, J=10.6, 9.0 Hz), 4.02 (m, 1H), 4.10 (t,2H, J=5.6 Hz), 4.17 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 7.53 (d, 2H, J=8.8Hz), 7.57 (s, 4H); MS (APCI) m/z 422 (M+H)⁺.

EXAMPLE 160N,N-dimethyl-N-[(3S)-1-(3-{1-[4′(1-pyrrolidinylcarbonyl)[1,1′-biphenyl]-4-yl]oxy}propyl)pyrrolidinyl]amine

[0616] 1-{[4′-(3-Chloropropoxy)[1,1′-biphenyl]-4-yl]carbonyl}pyrrolidineand N,N-dimethyl-N-[(3S)-pyrrolidinyl]amine were processed as describedin Example 159 to provide the title compound. ¹HNMR (500 MHz, CDCl₃) δ1.88 (m, 3H), 1.98 (m, 2H), 2.26 (m, 3H), 2.56 (m, 3H), 2.86 (s, 6H),3.45 (m, 5H), 3.70 (m, 3H), 3.84 (m, 1H), 4.03 (m, 1H), 4.10 (t, 2H,J=5.6 Hz), 4.19 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 7.53 (d, 2H, J=9.1 Hz),7.57 (s, 4H); MS (APCI) m/z 422 (M+H)⁺.

EXAMPLE 161(3R)-1-(3-{[4′-(1-pyrrolidinylcarbonyl)[1,1′-biphenyl]-4-yl]oxy}propyl)-3-pyrrolidinol

[0617] 1-{[4′-(3-Chloropropoxy)[1,1′-biphenyl]-4-yl]carbonyl}pyrrolidineand (3R)-3-pyrrolidinol were processed as described in Example 159 toprovide the title compound. ¹HNMR (500 MHz, CDCl₃) δ 1.82-2.02 (m, SH),2.03-2.50 (m, 16H), 2.96 (m, 2H), 3.14-3.44 (m, 5H), 3.49 (t, 2H, J=6.5Hz), 3.59 (m, 1H), 3.67 (t, 2H, J=6.9 Hz), 3.87 (m, 1H), 3.98 (m, 1H),4.06 (m, 1H), 4.12 (m, 1H), 4.64 (m, 1H), 6.94 (d, 2H, J=8.7 Hz), 7.53(d, 2H, J=8.7 Hz), 7.57 (s, 4H); MS (APCI) m/z 395 (M+H)⁺.

EXAMPLE 162N,N-dimethyl-N-[(3R)-1-(3-{4-[4-(1-pyrrolidinylcarbonyl)-1-piperazinyl]phenoxy}propyl)pyrrolidinyl]amine

[0618]1-[4-(3-chloropropoxy)phenyl]-4-(1-pyrrolidinylcarbonyl)piperazine andN,N-dimethyl-N-[(3R)-pyrrolidinyl]amine were processed as described inExample 159 to provide the title compound. ¹HNMR (500 MHz, CDCl₃) δ 1.86(m, 4H), 2.23 (m, 4H), 2.58 (m, 4H), 2.86 (s, 6H), 3.25 (m, 4H), 3.43(m, 6H), 3.61 (m, 4H), 3.72 (m, 1H), 3.85 (m, 1H), 4.05 (m, 3H), 4.18(m, 1H), 6.88 (d, 2H, J=9.0 Hz), 7.17 (d, 2H, J=9.0 Hz); MS (APCI) m/z430 (M+H)⁺.

EXAMPLE 163N,N-dimethyl-N-[(3S)-1-(3-{4-[4-(1-pyrrolidinylcarbonyl)-1-piperazinyllphenoxy]propyl}pyrrolidinyl]amine

[0619] [4-(3-chloropropoxy)phenyl]-4-(1-pyrrolidinylcarbonyl)piperazineand N,N-dimethyl-N-[(3S)-pyrrolidinyl]amine were processed as describedin Example 159 to provide the title compound. ¹HNMR (500 MHz, CDCl₃) δ1.86 (m, 4H), 2.22 (m, 4H), 2.57 (m, 4H), 2.86 (s, 6H), 3.25 (m, 4H),3.42 (m, 6H), 3.61 (m, 4H), 3.73 (m, IH), 3.85 (m, 1H), 4.04 (m, 3H),4.18 (m, 1H), 6.88 (d, 2H, J=9.0 Hz), 7.17 (d, 2H, J=9.0 Hz); MS (APCI)m/z 430 (M+H)⁺.

EXAMPLE 1644′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1′-biphenyl-4-carbonitrileEXAMPLE 164A 4′-methoxy-3-methyl-1,1′-biphenyl-4-carbonitrile

[0620] 4-Bromo-2-methylbenzonitrile (4.9 g, 25.0 mmol), Pd(PPh₃)₄ (578mg) in benzene (50 mL) and 2.0 M aqueous solution of Na₂CO₃ (25 mL, 50.0mmol) was treated with 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol)in ethanol (20 mL) and heated at 75° C. for 17 hours. The mixture wasallowed to cool to room temperature and the phases were separated. Theaqueous phase was extracted with diethyl ether (3×40 mL). The originalbenzene layer and the diethyl ether extracts were combined, filteredover celite, dried over sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography over silica using a mixture of hexane/CH₂Cl₂ (3:1) toprovide the title compound as a white powder (5.73 g, 85 % yield). ¹HNMR(300 MHz, CDCl₃) δ 2.35 (3H), 3.70 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI)m/z 224 (M+H)⁺.

EXAMPLE 164B 4′-hydroxy-3-methyl-1,1′-biphenyl-4-carbonitrile

[0621] The product from Example 164A (5.60 g, 25.4 mmol) in CH₂Cl₂ (120mL) at 78° C. was treated with 1.0 M BBr₃ (in CH₂Cl₂, 76 mL, 76.0 mmol)dropwise over 1 hour. After stirring for 14 hours at room temperature,the mixture was warmed to 0° C. (ice bath) and treated with water (0.5mL). After 10 minutes, additional water was added (2.0 mL), ice bath wasremoved, and 5.0 mL of water was added. The mixture was then treatedwith another 20 mL of water and allowed to stir for 45 minutes. Themixture was filtered and the filtrate extracted with CH₂Cl₂. The CH₂Cl₂layers were combined, dried over sodium sulfate, filtered, and thefiltrate concentrated under reduced pressure to provide the titlecompound as an off-white powder (5.04 g, 94% yield). ¹HNMR (300 MHz,CDCl₃) δ 2.35 (s, 3H), 5.0 (s, 1H), 6.79-7.50 (m, 7H); MS (DCI) m/z 210(M+H)⁺.

EXAMPLE 164C 4′-(3-chloroprolpoxy)-3-methyl-1,1′-biphenyl-4-carbonitrile

[0622] The product from Example 164B (0.5 g, 2.39 mmol),1-bromo-3-chloropropane (2.87 mmol, 451 mg) and K₂CO₃ (3.6 mmol, 495 mg)were combined in 2-butanone (25 mL) and heated at 110° C. After 16hours, the mixture was filtered and the filtrate evaporated underreduced pressure to provide the title compound (99% yield).

[0623] 1HNMR (300 MHz, CDCl₃) δ 2.23 (bs, 2H), 2.60 (s, 3H), 3.75 (bs,2H), 4.18 (bs, 2H), 6.85-7.64 (m, 7H); MS (DCI) m/z 286 (M+H)⁺.

EXAMPLE 164D4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1′-biphenyl-4-carbonitrile

[0624] The product from Example 164C (0.31 g, 1.08 mmol),(3R)-N,N-dimethyl-3-pyrrolidinamine (1.30 mmol, 149 mg), K₂CO₃ (1.62mmol, 224 mg) and KI (1.62 mmol, 268 mg) were combined in 2-butanone (20mL) and heated at 110° C. After 4 days, the solution was allowed to coolto room temperature, filtered, and the fitrate evaporated under reducedpressure. The residue was purified using silica gel chromatography(CHCl₃:MeOH:NH₄OH, 90:10:1) to provide a white solid (65% yield). ¹HNMR(300 MHz, CDCl₃) δ 1.60 (m, 2H), 1.80 (bs, 2H), 2.00-2.80 (m, 15H), 2.75(m, 1H), 4.10 (bs, 2H), 6.90-7.64 (m, 7H); MS (ESI) m/z 364 (M+H)⁺.

EXAMPLE 1654′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2-methyl-1,1′-biphenyl-4-carbonitrileEXAMPLE 165A 4′-methoxy-2-methyl-1,1′-biphenyl-4-carbonitrile

[0625] 4-Bromo-3-methylbenzonitrile and 4-methoxyphenylboronic acid wereprocessed as described in Example 164A to provide the title compound (80% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.40 (3H), 3.73 (s, 3H), 6.84-7.60(m, 7H); MS (DCI) m/z 224 (M+H)⁺.

EXAMPLE 165B 4′-hydroxy-2-methyl-1,1′-biphenyl-4-carbonitrile

[0626] The product from Example 165A and 1.0M BBr₃ were processed asdescribed in Example 164B to provide the title compound (98% yield).¹HNMR (300 MHz, CDCl₃) δ 2.42 (s, 3H), 5.2 (s, 1H), 6.70-7.54 (m, 7H);MS (DCI) m/z 210 (M+H)⁺.

EXAMPLE 165C 4′-(3-chloropropoxy)-2-methyl-1,1′-biphenyl-4-carbonitrile

[0627] The product from Example 165B and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(97% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.25 (bs, 5H), 3.80 (bs, 2H), 4.20(bs, 2H), 6.95-7.54 (m, 7H). MS (DCI) m/z 286 (M+H)⁺.

EXAMPLE 165D4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2-methyl-1,1′-biphenyl-4-carbonitrile

[0628] The product from Example 165C and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (55% yield). ¹HNMR (300 MHz,CDCl₃) δ 1.65 (m, 2H), 1.81 (bs, 2H), 2.00-2.85 (m, 15H), 3.0 (m, 1H),4.13 (bs, 2H), 6.90-7.54 (m, 7H); MS (ESI) m/z 364 (M+H)⁺.

EXAMPLE 1664′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl}propoxy]-3-fluoro-1,1′-biphenyl-4-carbonitrileEXAMPLE 166A 3-fluoro-4′-methoxy-1,1′-biphenyl-4-carbonitrile

[0629] 4-Bromo-2-fluorobenzonitrile and 4-methoxyphenylboronic acid wereprocessed as described in Example 164A to provide the title compound(82% yield). ¹HNMR (300 MHz, CDCl₃) δ 3.73 (s, 3H); MS (DCI) m/z 228(M+H)⁺.

EXAMPLE 166B 3-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbonitrile

[0630] The product from Example 166A and 1.0M BBr₃ were processed asdescribed in Example 164B to provide the title compound (95% yield).¹HNMR (300 MHz, CDCl₃) δ 4.95 (s, 3H), 6.80-7-55 (m, 7H); MS (DCI) m/z214 (M+H)⁺.

EXAMPLE 166C 4′-(3-chloropropoxy)-3-fluoro-1,1′-biphenyl-4-carbonitrile

[0631] The product from Example 166B and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(98% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.25 (m, 2H), 3.80 (m, 2H), 4.20(m, 2H), 7.00-7.65 (m, 7H); MS (DCI) m/z 290 (M+H)⁺.

EXAMPLE 166D4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-fluoro-1,1′-biphenyl-4-carbonitrile

[0632] The product from Example 166C and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (63% yield). ¹HNMR (300 MHz,CDCl₃) δ 1.68 (m, 2H), 2.15 (m 4H), 2.23 (s, 6H), 2.30-2.95 (m, 5H),4.15 (m, 2H), 7.00-7.63 (m, 7H); MS (ESI) m/z 368 (M+H)⁺.

EXAMPLE 1674′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-fluoro-1,1′-biphenyl-4-carbonitrileEXAMPLE 167A 3′-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbonitrile

[0633] 4-Cyanophenylboronic acid (0.92 g, 6.26 mmol),4-bromo-2-fluorophenol (1.0 g, 5.2 mmol), potassium phosphate tribasicmonohydrate (3.0g, 15.6 mmol) and Pd (Ph₃P)₂Cl₂ (73.0 mg, 0.1 mmol) werecombined in a mixture of IPA/H₂O (40 mL, 3:1) and heated at 70° C. After2 hours, the mixture was allowed to cool to room temperature and wasfiltered over celite. The filtrate was diluted with 150 ml of CH₂Cl₂ andwashed with water twice. The organic phase was dried over sodiumsulfate, filtered, and the filtrate concentrated under reduced pressure.The residue was chromatographed over silica gel using CH₂Cl₂ to providethe title compound as a white powder (0.61 g, 55 % yield). ¹HNMR (300MHz, CDCl₃) δ 5.20 (bs, 1H), 7.15-7.78 (m, 7H); MS (DCI) m/z 214 (M+H)⁺.

EXAMPLE 167B 4′-(3-chloropropoxy)-3′-fluoro-1,1′-biphenyl-4-carbonitrile

[0634] The product from Example 167A and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(99% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.30 (m, 2H), 3.80 (m, 2H), 4.25(m, 2H), 7.12-7.75 (m, 7H); MS (DCI) m/z 290 (M+H)⁺.

EXAMPLE 167C4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-fluoro-1,1′-biphenyl-4-carbonitrile

[0635] The product from Example 167B and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (60% yield). ¹HNMR (300 MHz,CDCl₃) δ 2.00-3.00 (m, 16H), 3.20 (m, 1H), 4.20 (m, 2H), 7.10-7.75 (m,7H); MS (ESI) m/z 368 (M+H)⁺.

EXAMPLE 1684′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-methyl-1,1′-biphenyl-4-carbonitrileEXAMPLE 168A 4′-hydroxy-3′-methyl-1,1′-biphenyl-4-carbonitrile

[0636] 4-Cyanophenylboronic acid and 4-bromo-2-methylphenol wereprocessed as described in Example 167A to provide the title compound(50% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.40 (s, 3H), 4.85 (bs, 1H),6.83-7.65 (m, 7H); MS (CDI) m/z 210 (M+H)⁺.

EXAMPLE 168B 4′-(3-chloropropoxy)-3′-methyl-1,1′-biphenyl-4-carbonitrile

[0637] The product from Example 168A and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(90% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.25 (m, 5H), 3.85 (m, 2H), 4.20(m, 2H), 6.90-7.65 (m, 7H); MS (CDI) m/z 286 (M+H)⁺.

EXAMPLE 168C4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-methyl-1,1′-biphenyl-4-carbonitrile

[0638] The product from Example 168B and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (58% yield). ¹HNMR (300 MHz,CDCl₃) δ 1.85 (m, 1H), 2.15 (m, 4H), 2.24 (s, 3H), 2.30 (s, 6H),2.50-2.85 (m, 5H), 3.00 (m, 1H), 4.10 (m, 2H), 6.88-7.65 (m, 7H); MS(ESI) m/z 364 (M+H)⁺.

EXAMPLE 169 4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-iodo-1,1′-biphenyl-4-carbonitrile EXAMPLE 169A4′-hydroxy-3′-iodo-1,1′-biphenyl-4-carbonitrile

[0639] 4′-Hydroxy-1,1′-biphenyl-4-carbonitrile (25.0 g, 128 mmol),purchased commercially, NaI (19.19 g, 128 mmol), and sodium hydroxide(5.12g, 128 mmol) were combined in methanol (500 mL) at 0° C. andtreated with bleach (5.25%, 181.0 g) dropwise over 1 hour. Afterstirring at 0° C. for 1 hour, the mixture was treated with 10% aqueoussodium thiosulfate (250 mL). The mixture was adjusted to pH 6.8 with 10%aqueous HCl and then the mixture was filtered. The filter cake wascrystallized from hot CH₂Cl₂/hexane to provide the title compound (40%yield). ¹HNMR (300 MHz, CDCl₃) δ 5.40 (s, 1H), 7.10 (m, 1H), 7.50 (m,1H), 7.60 (m, 2H), 7.77(m, 2H), 7.90 (m, 1H); MS (CDI) m/z 339 (M+NH₄)⁺.

EXAMPLE 169B 4′-(3-chloropropoxy)-3′-iodo-1,1′-biphenyl-4-carbonitrile

[0640] The product from Example 169A and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(100% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.30 (s, 2H), 3.85 (m, 2H), 4.25(m, 2H), 6.90 (m, 1H), 7.55 (m, 1H), 7.60 (m, 2H), 7.73(m, 2H), 8.0 (m,1H); MS (CDI) m/z 398 (M+H)⁺.

EXAMPLE 169C4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-iodo-1,1′-biphenyl-4-carbonitrile

[0641] The product from Example 169B and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (65% yield). ¹HNMR (300 MHz,CDCl₃) δ 1.85 (m, 1H), 2.15 (m, 4H), 2.30 (s, 6H), 2.50-2.85 (m, 5H),3.00 (m, 1H), 4.10 (m, 2H), 6.88 (m, 1H), 7.50 (m, 1H), 7.62 (m, 2H),7.76(m, 2H), 8.05 (m, 1H); MS (ESI) m/z 476 (M+H)⁺.

EXAMPLE 1704′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2′-methyl-1,1′-biphenyl-4-carbonitrileEXAMPLE 170A 4′-hydroxy-2′-methyl-1,1′-biphenyl-4-carbonitrile

[0642] 4-Cyanophenylboronic acid and 4-bromo-3-methylphenol wereprocessed as described in Example 167A to provide the title compound(60% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.20 (s, 3H), 4.68 (bs, 1H), 6.78(m, 2H), 7.15 (m, 1H), 7.42 (m, 2H), 7.76(m, 2H); MS (CDI) m/z 227(M+NH₄)⁺.

EXAMPLE 170B 4′-(3-chloropropoxy)-2′-methyl-1,1′-biphenyl-4-carbonitrile

[0643] The product from Example 170A and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(90% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.25 (m, 5H), 3.73 (m, 2H), 4.18(m, 2H), 6.80 (m, 2H), 7.15 (m, 1H), 7.40 (m, 2H), 7.66(m, 2H); MS (CDI)m/z 286 (M+H)⁺.

EXAMPLE 170C4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2′-methyl-1,1′-biphenyl-4-carbonitrile

[0644] The product from Example 170B and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (90% yield). ¹HNMR (300 MHz,CDCl₃) δ 1.65 (m, 1H), 1.88 (m, 4H), 2.20 (s, 3H), 2.22-3.80 (m, 12H),4.10 (m, 2H), 6.80 (m, 2H), 7.18 (m, 1H), 7.40 (m, 2H), 7.70 (m, 2H); MS(ESI) m/z 364 (M+H)⁺.

EXAMPLE 1713′-chloro-4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-1,1′-biphenyl-4-carbonitrileEXAMPLE 171A 3′-chloro-4′-hydroxy-1,1′-biphenyl-4-carbonitrile

[0645] 4-Cyanophenylboronic acid and 4-bromo-2-chlorophenol wereprocessed as described in Example 167A to provide the title compound(62% yield). ¹HNMR (300 MHz, DMSO) δ 7.12 (m, 1H), 7.58 (m, 1H), 7.80(m, 5H); MS (CDI) m/z 247(M+NH₄)⁺.

EXAMPLE 171B 3′-chloro-4′-(3-chloropropoxy)-1,1′-biphenyl-4-carbonitrile

[0646] The product from Example 171A and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(92% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.30 (m, 2H), 3.80 (m, 2H), 4.20(m, 2H), 7.02 (m, 1H), 7.42 (m, 1H), 7.80 (m, 5H); MS (CDI) m/z307(M+H)⁺.

EXAMPLE 171C3′-chloro-4′-4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-1,1′-biphenyl-4-carbonitrile

[0647] The product from Example 171B and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (42% yield). ¹HNMR (300 MHz,CDCl₃) δ 2.00-3.60 (m, 17H), 4.20 (m, 2H), 7.00 (m, 1H), 7.45 (m, 1H),7.70 (m, 5H); MS (ESI) m/z 384(M+H)⁺.

EXAMPLE 1724′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′,5′-difluoro-1,1′-biphenyl-4-carbonitrileEXAMPLE 172A 3′,5′-difluoro-4′-hydroxy-1,1′-biphenyl-4-carbonitrile

[0648] 4-Cyanophenylboronic acid and 4-bromo-2,6-difluorophenol wereprocessed as described in Example 167A to provide the title compound(48% yield). ¹HNMR (300 MHz, CDCl₃) δ 5.30 (bs, 1H), 7.20 (m, 2H), 7.60(m, 2H), 7.78 (m, 2H); MS (CDI) m/z 232(M+H)⁺.

EXAMPLE 172B4′-(3-chloropropoxy)-3′,5′-difluoro-1,1′-biphenyl-4-carbonitrile

[0649] The product from Example 172A and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(100% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.30 (m, 2H), 3.80 (m, 2H), 4.40(m, 2H), 7.15 (m, 2H), 7.60 (m, 2H), 7.80 (m, 2H); MS (CDI) m/z 308(M+H)⁺.

EXAMPLE 172C4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′,5′-difluoro-1,1′-biphenyl-4-carbonitrile

[0650] The product from Example 172B and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (66% yield). ¹HNMR (300 MHz,CDCl₃) δ 2.00-3.60 (m, 17H), 4.25 (m, 2H), 7.17 (m, 2H), 7.60 (m, 2H),7.78 (m, 2H); MS (ESI) m/z 386 (M+H)⁺.

EXAMPLE 1734′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-methoxy-1,1′-biphenyl-4-carbonitrileEXAMPLE 173A 4-hydroxy-3′-methoxy-1,1′-biphenyl-4-carbonitrile

[0651] 4-Cyanophenylboronic acid and 4-bromo-2-methoxyphenol wereprocessed as described in Example 167A to provide the title compound(63% yield). ¹HNMR (300 MHz, CDCl₃) δ 3.96 (s, 3H), 5.80 (s, 1H), 7.17(m, 3H), 7.64 (m, 4H); MS (CDI) m/z 226 (M+H)⁺.

EXAMPLE 173B4′-(3-chloropropoxy)-3′-methoxy-1,1′-biphenyl-4-carbonitrile

[0652] The product from Example 173A and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(97% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.30 (m, 2H), 3.80 (m, 2H), 3.98(s, 3H), 4.40 (m, 2H), 7.10 (m, 3H), 7.63 (m, 4H); MS (CDI) m/z 302(M+H)⁺.

EXAMPLE 173C4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-methoxy-1,1′-biphenyl-4-carbonitrile

[0653] The product from Example 173B and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (60% yield). ¹HNMR (300 MHz,CDCl₃) δ 1.78 (m, 1H), 2.15 (m, 3H), 2.25 (s, 6H), 2.27-2-95 (m, 7H),3.92 9s, 3H), 4.18 9m, 2H), 6.93 (m, 1H), 7.15 (m, 2H), 7.68 (m, 4H); MS(ESI) m/z 380 (M+H)⁺.

EXAMPLE 1743′-chloro-4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-5′-fluoro-1,1′-biphenyl-4-carbonitrileEXAMPLE 174A 3′-chloro-5′-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbonitrile

[0654] 4-Cyanophenylboronic acid and 4-bromo-2-chloro-6-fluorophenolwere processed as described in Example 167A to provide the titlecompound (48% yield). ¹HNMR (300 MHz, MeOD) δ 7.40 (m, 1H), 7.52 (m,1H), 7.78 (s, 4H); MS (CDI) m/z 248 (M+H)⁺.

EXAMPLE 174B3′-chloro-4′-(3-chloropropoxy)-5′-fluoro-1,1′-biphenyl-4-carbonitrile

[0655] The product from Example 174A and 1-bromo-3-chloropropane wereprocessed as described in Example 164C to provide the title compound(100% yield). ¹HNMR (300 MHz, CDCl₃) δ 2.30 (m, 2H), 3.80 (m, 2H), 4.40(m, 2H), 7.20 (m, 1H), 7.40 (m, 1H), 7.70 (m, 4H); MS (CDI) m/z 325(M+H)⁺.

EXAMPLE 174C3′-chloro-4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-5′-fluoro-1,1′-biphenyl-4-carbonitrile

[0656] The product from Example 174B and(3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described inExample 164D to provide the title compound (66% yield). ¹HNMR (300 MHz,CDCl₃) δ 2.00-3.60 (m, 17H), 4.22 (m, 2H), 7.20 (m, 1H), 7.40 (m, 1H),7.60 (m, 2H), 7.75 (m, 2H); MS (ESI) m/z 402 (M+H)⁺.

Determination of Biological Activity Histamine-3 Receptor Binding

[0657] To determine the effectiveness of representative compounds ofthis invention as histamine-3 receptor ligands (H₃ receptor ligands),the following tests were conducted according to methods previouslydescribed (European Journal of Pharmacology, 188:219-227 (1990); Journalof Pharmacology and Experimental Therapeutics, 275: 598-604 (1995);Journal of Pharmacology and Experimental Therapeutics, 276:1009-1015(1996); and Biochemical Pharmacology, 22: 3099-3108 (1973)).

[0658] Briefly, male Sprague-Dawley rat brain cortices were homogenized(1 g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containingprotease inhibitor cocktail (Calbiochem) using a polytron set at 20,500rpm. Homogenates were centrifuged for 20 minutes at 40,000× g. Thesupernatant was decanted, and pellets were weighed. The pellet wasresuspended by polytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTAwith protease inhibitors and centrifuged for 20 minutes at 40,000× g.The membrane pellet was resuspended in 6.25 volumes (per gram wet weightof pellet) of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors andaliquots flash frozen in liquid N₂ and stored at −70° C. until used inassays. Rat cortical membranes (12 mg wet weight/tube) were incubatedwith (³H)-N-α-methylhistamine (˜0.6 nM) with or without H₃ receptorantagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5mM EDTA (pH 7.7). Test compounds were dissolved in DMSO to provide 20 mMsolution, serially diluted and then added to the incubation mixturesprior to initiating the incubation assay by addition of the membranes.Thioperamide (3 μM) was used to determine nonspecific binding. Bindingincubations were conducted for 30 minutes at 25° C. and terminated byaddition of 2 mL of ice cold 50 mM Tris-HCl (pH 7.7) and filtrationthrough 0.3% polyethylenimine-soaked Unifilter plates (Packard). Thesefilters were washed 4 additional times with 2 mL of ice-cold 50 mMTris-HCl and dried for 1 hour. Radioactivity was determined using liquidscintillation counting techniques. Results were analyzed by Hilltransformation and Ki values were determined using the Cheng-Prusoffequation. TABLE 1 Example Number Ki (nM) 1 105 2 68 3 37 4 55 5 6.3 6 957 31 8 1721 9 675 10 626 11 4.0 12 71 13 50 14 40 15 7.3 16 67 17 13 1829 19 3.8 20 12 21 22 22 12 23 33 24 43 25 30 26 57 27 18 28 16 29 5.930 10 31 30 32 99 33 16 34 11 35 13 36 12 37 349 38 132 39 7.6 40 51 4148 42 8.8 43 37 44 52 45 127 46 103 47 12 48 60 49 13 50 60 51 9.3 52 1553 3.9 54 98 55 2.9 56 4.7 57 3.6 58 3.9 59 3.0 60 5.2 61 4.2 62 6.4 6312 64 11 65 5.0 66 4.6 67 2.9 68 2.8 69 3.7 70 3.0 71 2.8 72 7.9 73 6.474 5.6 75 19 76 4.9 77 5.3 78 8.7 79 7.9 80 10 81 5.0 82 21 83 23 84 9.585 5.3 86 1.8 87 4.9 88 6.8 89 11 90 11 91 2.8 92 4.9 93 3.2 94 4.9 954.6 96 1.2 97 6.7 98 90 99 63 100 1634 101 179 102 112 103 195 104 173105 725 106 168 107 200 108 12 109 26 110 30 111 11 112 13 113 13 114 65115 21 116 14 117 45 118 5.7 119 7.7 120 10 121 16 122 20 123 5.6 1242.9 125 7.4 126 4.6 127 16 128 2.3 129 192 130 31 131 51 132 74 133 57134 168 135 132 136 215 137 196 138 118 139 288 140 220 141 342 142 321143 85 144 21 145 9.6 146 3.0 147 209 148 291 149 329 150 267 151 22 1528.7 153 42 154 63 155 105 156 45 157 593 158 15 164 48 165 17 166 73 1679 168 74 169 206 170 51 171 41 172 13 173 27 174 14

[0659] As shown by the compounds of the present invention bind to thehistamine-3 receptor and therefore may have utility in the treatment ofdiseases or conditions ameliorated with histamine-3 ligands.

[0660] Compounds of the present invention are histamine-3 receptorligands that modulate function of the histamine-3 receptor byantagonizing the activity of the receptor. These compounds may beinverse agonists that inhibit the basal activity of the receptor or theymay by antagonists that completely block the action ofreceptor-activating agonists. These compounds may also be partialagonists that partially block or partially activate the histamine-3receptor receptor or they may be agonists that activate the receptor.

[0661] Compounds of the present invention may exist as stereoisomerswherein, asymmetric or chiral centers are present. These stereoisomersare “R” or “S” depending on the configuration of substituents around thechiral carbon atom. The terms “R” and “S” used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. In particular, thestereochemistry at the point of attachment of R₆ and R₉, as shown informula I-VII, may independently be either (R) or (S), unlessspecifically noted otherwise. Additionally, the 3-position of thepyrrolidine ring of formula I-VII may independently be either (R) or(S), unless specifically noted otherwise. The preferred stereochemistryat the 3-position of the pyrrolidine ring is the (R) configuration forcompounds of the present invention. However, the present invention doescontemplate various stereoisomers and mixtures thereof and arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the presentinvention may be prepared synthetically from commercially availablestarting materials which contain asymmetric or chiral centers or bypreparation of racemic mixtures followed by resolution well-known tothose of ordinary skill in the art. These methods of resolution areexemplified by (1) attachment of a mixture of enantiomers to a chiralauxiliary, separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary or (2) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns.

[0662] The term “pharmaceutically acceptable carrier,” as used herein,means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of one skilled in the art of formulations.

[0663] The present invention provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions can be formulated for oral administration insolid or liquid form, for parenteral injection or for rectaladministration.

[0664] Further included within the scope of the present invention arepharmaceutical compositions comprising one or more of the compounds offormula I-VII prepared and formulated in combination with one or morenon-toxic pharmaceutically acceptable compositions. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

[0665] The pharmaceutical compositions of this invention can beadministered to humans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

[0666] Pharmaceutical compositions of this invention for parenteralinjection comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions and sterilepowders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols(propylene glycol, polyethylene glycol, glycerol, and the like),suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity may bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants.

[0667] These compositions may also contain adjuvants such aspreservative agents, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of microorganisms may be ensured byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

[0668] In some cases, in order to prolong the effect of a drug, it isoften desirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

[0669] Suspensions, in addition to the active compounds, may containsuspending agents, as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, andmixtures thereof.

[0670] If desired, and for more effective distribution, the compounds ofthe present invention can be incorporated into slow-release ortargeted-delivery systems such as polymer matrices, liposomes, andmicrospheres. They may be sterilized, for example, by filtration througha bacteria-retaining filter or by incorporation of sterilizing agents inthe form of sterile solid compositions, which may be dissolved insterile water or some other sterile injectable medium immediately beforeuse.

[0671] The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more excipients as noted above. The soliddosage forms of tablets, dragees, capsules, pills, and granules can beprepared with coatings and shells such as enteric coatings, releasecontrolling coatings and other coatings well known in the pharmaceuticalformulating art. In such solid dosage forms the active compound can beadmixed with at least one inert diluent such as sucrose, lactose, orstarch. Such dosage forms may also comprise, as is normal practice,additional substances other than inert diluents, e.g., tabletinglubricants and other tableting aids such a magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets and pills,the dosage forms may also comprise buffering agents. They may optionallycontain opacifying agents and can also be of such composition that theyrelease the active ingredient(s) only, or preferentially, in a certainpart of the intestinal tract in a delayed manner. Examples of embeddingcompositions which can be used include polymeric substances and waxes.

[0672] Injectable depot forms are made by forming microencapsulatedmatrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides) Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

[0673] The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

[0674] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

[0675] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound is mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

[0676] Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugar as well as high molecular weight polyethyleneglycols and the like.

[0677] The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of embedding compositions which can be used includepolymeric substances and waxes.

[0678] Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

[0679] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

[0680] Besides inert diluents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

[0681] Dosage forms for topical or transdermal administration of acompound of this invention include ointments, pastes, creams, lotions,gels, powders, solutions, sprays, inhalants or patches. The activecomponent is admixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives or buffers as may berequired. Ophthalmic formulation, ear drops, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

[0682] The ointments, pastes, creams and gels may contain, in additionto an active compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

[0683] Powders and sprays can contain, in addition to the compounds ofthis invention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

[0684] Compounds of the present invention may also be administered inthe form of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes may beused. The present compositions in liposome form may contain, in additionto the compounds of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the natural andsynthetic phospholipids and phosphatidylcholines (lecithins) usedseparately or together.

[0685] Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

[0686] The terms “pharmaceutically acceptable salts, esters and amides,”as used herein, refer to carboxylate salts, amino acid addition salts,zwitterions, esters and amides of compounds of formula I-VII which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, are commensurate with areasonable benefit/risk ratio, and are effective for their intended use.

[0687] The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. By “pharmaceutically acceptable salt” is meant those salts whichare, within the scope of sound medical judgement, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention or separately by reacting a free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate,hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Also, the basicnitrogen-containing groups can be quatemized with such agents as loweralkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

[0688] Basic addition salts can be prepared in situ during the finalisolation and purification of compounds of this invention by reacting acarboxylic acid-containing moiety with a suitable base such as thehydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas lithium, sodium, potassium, calcium, magnesium and aluminum salts andthe like and nontoxic quaternary ammonia and amine cations includingammonium, tetramethylammonium, tetraethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamineand the like. Other representative organic amines useful for theformation of base addition salts include ethylenediamine, ethanolamine,diethanolamine, piperidine, piperazine and the like. Preferred salts ofthe compounds of the invention include phosphate, tris and acetate.

[0689] The term “pharmaceutically acceptable ester,” as used herein,refers to esters of compounds of the present invention which hydrolyzein vivo and include those that break down readily in the human body toleave the parent compound or a salt thereof. Examples ofpharmaceutically acceptable, non-toxic esters of the present inventioninclude C₁-to-C₆ alkyl esters and C₅-to-C₇ cycloalkyl esters, althoughC₁-to-C₄ alkyl esters are preferred. Esters of the compounds of formulaI-VII may be prepared according to conventional methods.

[0690] The term “pharmaceutically acceptable amide,” as used herein,refers to non-toxic amides of the present invention derived fromammonia, primary C₁-to-C₆ alkyl amines and secondary C₁-to-C₆ dialkylamines. In the case of secondary amines, the amine may also be in theform of a 5- or 6-membered heterocycle containing one nitrogen atom.Amides derived from ammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂dialkyl secondary amides are preferred. Amides of the compounds offormula I-VII may be prepared according to conventional methods.

[0691] The term “pharmaceutically acceptable prodrug” or “prodrug,” asused herein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use. Prodrugs of the present invention may be rapidlytransformed in vivo to a parent compound of formula I-VII, for example,by hydrolysis in blood. A thorough discussion is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S.Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987), hereby incorporated by reference. Representative examples ofprodrugs of the present invention include, but are not limited to,(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl methylsulfate,(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl diethylphosphate, (3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl acetate,(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyldimethylcarbamate, and(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl methylcarbonate.

[0692] Dosage forms for topical administration of a compound of thisinvention include powders, sprays, ointments and inhalants. The activecompound is mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers or propellantswhich can be required. Opthalmic formulations, eye ointments, powdersand solutions are also contemplated as being within the scope of thisinvention.

[0693] Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

[0694] The present invention contemplates pharmaceutically activecompounds either chemically synthesized or formed by in vivobiotransformation to compounds of formula I-VII.

[0695] The compounds of the present invention, including but not limitedto those specified in the examples, possess an affinity for thehistamine-3 receptors. As histamine-3 receptor ligands, the compounds ofthe present invention may be useful for the treatment and prevention ofdiseases or conditions such as acute myocardial infarction, Alzheimer'sdisease, attention-deficit hyperactivity disorder, bipolar disorder,cognitive enhancement, cognitive deficits in psychiatric disorder, drugabuse, deficits of memory and learning, jet lag, Parkinson's disease,epilepsy, schizophrenia, dementia, depression, cutaneous carcinoma, mildcognitive impairment, medullary thyroid carcinoma, melanoma, asthma,narcolepsy, mood and attention alteration, Meniere's disease,gastrointestinal disorders, inflammation, migraine, motion sickness,neurogenic inflammation, obsessive compulsive disorder, Tourette'ssyndrome, obesity, pain, seizures, septic shock, vertigo, andwakefulness.

[0696] The ability of the compounds of the present invention, includingbut not limited to those specified in the examples, to treat septicshock and cardiovascular disorders, in particular, acute myocardialinfarction may be demonstrated by (Imamura et al., Circ.Res., (1996) 78,475-481; Imamura et. al., Circ.Res., (1996) 78, 863-869; R. Levi and N.C. E. Smith, “Histamine H₃-receptors: A new frontier in myocardialischemia”, J. Pharm. Exp. Ther., 292: 825-830, (2000); and Hatta, E., KYasuda and R. Levi, “Activation of histamine H₃ receptors inhibitscarrier-mediated norepinephrine release in a human model of protractedmyocradial ischemia”, J. Pharm. Exp. Ther., 283: 494-500, (1997)).

[0697] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat sleep disorders, inparticular, narcolepsy may be demonstrated by (Lin et al., Brain Res.(1990) 523, 325-330; Monti et al., Neuropsychopharmacology (1996) 15,31-35; Sakai, et al., Life Sci. (1991) 48, 2397-2404;Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989)67, 75-78; Panula, P. et al., Neuroscience (1998) 44, 465-481); Wada etal., Trends in Neuroscience (1991) 14, 415); and Monti et al., Eur. J.Pharmacol. (1991) 205, 283).

[0698] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat cognition andmemory process disorders may be demonstrated by (Mazurkiewicz-Kwileckiand Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78; Panula, P. etal., Neuroscience (1997) vol. 82, 993-997; Haas et al., Behav. BrainRes. (1995) 66, 41-44; De Almeida and Izquierdo, Arch. Int. Pharmacodyn.(1986) 283, 193-198; Kamei et al., Psychopharmacology (1990) 102,312-318; and Kamei and Sakata, Jpn. J. Pharmacol. (1991) 57, 437-482);Schwartz et al., Psychopharmacology; The fourth Generation of Progress.Bloom and Kupfer (eds). Raven Press, New York, (1995) 397; and Wada etal., Trends in Neurosci., (1991) 14, 415).

[0699] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat attention-deficithyperactivity disorder (ADHD) may be demonstrated by (Shaywitz et al.,Psychopharmacology (1984) 82, 73-77; Dumery and Blozovski, Exp. BrainRes. (1987) 67, 61-69; Tedford et al., J. Pharmacol. Exp. Ther. (1995)275, 598-604; and Tedford et al., Soc. Neurosci. Abstr. (1996) 22, 22).

[0700] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat seizures, inparticular, epilepsy may be demonstrated by (Yokoyama et al., Eur. J.Pharmacol. (1993) 234, 129; Yokoyama and linuma, CNS Drugs (1996) 5,321; Onodera et al., Prog. Neurobiol. (1994) 42, 685; R. Leurs, R. C.Vollinga and H. Timmerman, “The medicinal chemistry and therapeuticpotentials of ligand of the histamine H₃ receptor”, Progress in DrugResearch 45: 170-165, (1995); Leurs and Timmerman, Prog. Drug Res.(1992) 39, 127; The Histamine H₃ Receptor, Leurs and Timmerman (eds),Elsevier Science, Amsterdam, The Netherlands (1998); H. Yokoyama and K.linuma, “Histamine and Seizures: Implications for the treatment ofepilepsy”, CNS Drugs, 5(5); 321-330, (1995); and K. Hurukami, H.Yokoyama, K. Onodera, K. linuma and T. Watanabe, AQ-0145, “A newlydeveloped histamine H₃ antagonist, decreased seizure susceptibility ofeletrically induced convulsions in mice”, Meth. Find. Exp. Clin.Pharmacol., 17(C): 70-73, (1995)).

[0701] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat motion sickness,Alzheimer's disease, and Parkinson's disease may be demonstrated by(Onodera et al., Prog. Neurobiol. (1994) 42, 685; Leurs and Timmerman,Prog. Drug Res. (1992) 39, 127; and The Histamine H₃ Receptor, Leurs andTimmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998)).

[0702] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat wakefulness,cognitive enhancement, mood and attention alteration, vertigo and motionsickness, and treatment of cognitive deficits in psychiatric disordermay be demonstrated by (Schwartz, Physiol. Review (1991) 71, p. 1-51).

[0703] The ability of the compounds of the present invention, includingbut not limited to those specified in the examples, to treat mildcognitive impairment, deficits of memory, deficits of learning anddementia may be demonstrated by (C. E. Tedford, in “The Histamine H₃Receptor: a target for new drugs”, the Pharmacochemistry Library, vol.30 (1998) edited by R. Leurs and H. Timmerman, Elsevier (New York). p.269 and references also contained therein.)

[0704] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat narcolepsy,schizophrenia, depression, and dementia may be demonstrated by (R.Leurs, R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potentials of ligand of the histamine H₃ receptor”, Progressin Drug Research 45: 170-165, (1995); The Histamine H₃ Receptor, Leursand Timmerman (eds), Elsevier Science, Amsterdam, The Netherlands(1998); and Perez-Garcia C, et. al., Laboratory of Pharmacology,University of San Pablo CEU, Madrid, Spain, Psychopharmacology (Berl)(1999) Feb., 142(2): 215-20).

[0705] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat obesity may bedemonstrated by (Leurs et al., Trends in Pharm. Sci. (1998) 19, 177-183;Anti-Obesity: Biological Psychiatry Table of Contents Volume 45/Number4/Feb. 15, 1999 page 475, Thioperamide, a Histamine H₃ ReceptorAntagonist, Powerfully Suppresses Peptide YY-Induced Food Intake inRats, Etsuro Itoh, Mineko Fujimiya and Akio Inui; Sakata, ObesityResearch (1995) 3, S 541-548; E. Schlicker and M. Kathmann, in “TheHistamine H₃ Receptor: a target for new drugs”, the PharmacochemistryLibrary, vol. 30 (1998) edited by R. Leurs and H. Timmerman, Elsevier(New York). p. 13 and references also contained therein; and Schwartz,Physiol. Review (1991) 71, p. 1-51).

[0706] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat inflammation andpain may be demonstrated by (Phillips et al., Annual Reports inMedicinal Chemistry (1998) 33, 31-40).

[0707] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat migraine may bedemonstrated by (R. Leurs, R. C. Vollinga and H. Timmerman, “Themedicinal chemistry and therapeutic potentials of ligand of thehistamine H₃ receptor”, Progress in Drug Research 45: 170-165, (1995);and Matsubara et al., Eur. J. Pharmacol. (1992) 224, 145; and Rouleau etal., J. Pharmacol. Exp. Ther. (1997) 281, 1085).

[0708] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat cancer, inparticular, melanoma, cutaneous carcinoma and medullary thyroidcarcinoma may be demonstrated by (Polish Med. Sci. Mon., (1998) vol. 4,issue 5, 747; Adam Szelag, “Role of histamine H₃-receptors in theproliferation of neoplastic cells in vitro”, Med. Sci. Monit., 4(5):747-755, (1998); and Fitzsimons, C., H. Duran, F. Labombarda, B.Molinari and E. Rivera, “Histamine receptors signalling in epidermaltumor cell lines with H-ras gene alterations”, Inflammation Res., 47(Suppl 1): S50-S51, (1998)).

[0709] The ability of the compounds of the invention, including but notlimited to those specified in the examples, to treat vestibulardysfunctions, in particular, Meniere's disease may be demonstrated by(R. Leurs, R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potentials of ligand of the histamine H₃ receptor”, Progressin Drug Research 45: 170-165, (1995).

[0710] The ability of the compounds of the present invention, includingbut not limited to those specified in the examples, to treat asthma maybe demonstrated by (Delaunois A., Gustin P., Garbarg M., and Ansay M.,“Modulation of acetylcholine, capsaicin and substance P effects byhistamine H₃ receptors in isolated perfused rabbit lungs”, EuropeanJournal of Pharmacology 277(2-3):243-50, (1995); and (Dimitriadou, etal., “Functional relationship between mast cells and C-sensitive nervefibres evidenced by histamine H₃-receptor modulation in rat lung andspleen”, Clinical Science. 87(2):151-63, (1994).

[0711] Aqueous liquid compositions of the present invention areparticularly useful for the treatment and prevention of asthma,epilepsy, Raynaud's syndrome, male sexual dysfunction, female sexualdysfunction, migraine, pain, eating disorders, urinary incontinence,functional bowel disorders, neurodegeneration and stroke.

[0712] When used in the above or other treatments, a therapeuticallyeffective amount of one of the compounds of the present invention can beemployed in pure form or, where such forms exist, in pharmaceuticallyacceptable salt, ester, amide or prodrug form. Alternatively, thecompound can be administered as a pharmaceutical composition containingthe compound of interest in combination with one or morepharmaceutically acceptable excipients. The phrase “therapeuticallyeffective amount” of the compound of the invention means a sufficientamount of the compound to treat disorders, at a reasonable benefit/riskratio applicable to any medical treatment. It will be understood,however, that the total daily usage of the compounds and compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgement. The specific therapeuticallyeffective dose level for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of the compound at levels lower than required to achieve thedesired therapeutic effect and to gradually increase the dosage untilthe desired effect is achieved.

[0713] The total daily dose of the compounds of this inventionadministered to a human or lower animal may range from about 0.003 toabout 10 mg/kg/day. For purposes of oral administration, more preferabledoses can be in the range of from about 0.01 to about 5 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

What is claimed is:
 1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein Z is selectedfrom the group consisting of a covalent bond and CH₂; R₁ is selectedfrom the group consisting of OR₂, NR₃R₄ and

R₂ is selected from the group consisting of hydrogen, alkoxycarbonyl,alkyl, alkylcarbonyl, aminocarbonyl, sulfono and phosphono; R₃ and R₄are independently selected from the group consisting of hydrogen,alkenyl, alkenylcarbonyl, alkenyloxycarbonyl, alkenylsulfonyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl,alkynylcarbonyl, alkynyloxycarbonyl, alkynylsulfonyl, aminocarbonyl,aminosulfonyl, arylalkyl, arylalkenylcarbonyl, arylalkenylsulfonyl,arylalkylcarbonyl, arylalkylsulfonyl, arylarylcarbonyl,arylarylsulfonyl, arylcarbonyl, arylheterocylecarbonyl,arylheterocylesulfonyl, aryloxyarylcarbonyl, aryloxyarylsulfonyl,arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl,cycloalkylalkylsulfonyl, cycloalkylcarbonyl, cycloalkylsulfonyl, formyl,heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl,heterocyclealkylsulfonyl, heterocyclearylcarbonyl,heterocyclearylsulfonyl, heterocyclecarbonyl,heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl,heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl,heterocycleoxyarylsulfonyl, heterocyclesulfonyl, andheterocyclethioalkylcarbonyl; R₅ and R₆ are independently selected fromthe group consisting of hydrogen and alkyl; R₇ is selected from thegroup consisting of hydrogen and alkyl; or R₁ and R₇ together form (═O);R₈ is selected from the group consisting of alkylcarbonyl, aryl,arylcarbonyl, arylcarbonylaryl, arylcarbonylheterocycle,cycloalkylcarbonyl, cycloalkylcarbonylaryl,cycloalkylcarbonylheterocycle, heterocycle, heterocyclecarbonyl,heterocyclecarbonylaryl, heterocyclecarbonylheterocycle; R₉ is selectedfrom the group consisting of hydrogen and lower alkyl; R_(A), R_(B),R_(C) and R_(D) are independently selected from the group consisting ofhydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl,alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, carboxy,carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, mercapto and nitro; wherein at each occurrence ofsaid aryl, arylalkenylcarbonyl, arylalkenylsulfonyl, arylalkylcarbonyl,arylalkylsulfonyl, arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl,arylcarbonylaryl, arylcarbonylheterocycle, arylheterocylecarbonyl,arylheterocylesulfonyl, aryloxyarylcarbonyl, aryloxyarylsulfonyl,arylsulfonyl, cycloalkylcarbonylaryl, heterocyclearylcarbonyl,heterocyclearylsulfonyl, heterocyclecarbonylaryl,heterocycleoxyarylcarbonyl, and heterocycleoxyarylsulfonyl, the arylportion can be optionally substituted with 1, 2, or 3 substituentsselected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy,alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl,aminocarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl,halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto andnitro; and wherein at each occurrence of said arylcarbonylheterocycle,arylheterocylecarbonyl, arylheterocylesulfonyl,cycloalkylcarbonylheterocycle, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclealkylsulfonyl,heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl,heterocyclecarbonylaryl, heterocyclecarbonylheterocycle,heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl,heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl,heterocycleoxyarylsulfonyl, heterocyclesulfonyl, andheterocyclethioalkylcarbonyl, the heterocycle portion can be optionallysubstituted with 1, 2, or 3 substituents selected from the groupconsisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl,alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl,aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl,halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto andnitro.
 2. A compound according to claim 1 wherein R₁ is NR₃R4; R₃ and R₄are independently selected from the group consisting of hydrogen,alkenyl, alkenylcarbonyl, alkenyloxycarbonyl, alkenylsulfonyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl,alkynylcarbonyl, alkynyloxycarbonyl, alkynylsulfonyl, aminocarbonyl,aminosulfonyl, arylalkyl, arylalkenylcarbonyl, arylalkenylsulfonyl,arylalkylcarbonyl, arylalkylsulfonyl, arylarylcarbonyl,arylarylsulfonyl, arylcarbonyl, arylheterocylecarbonyl,arylheterocylesulfonyl, aryloxyarylcarbonyl, aryloxyarylsulfonyl,arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl,cycloalkylalkylsulfonyl, cycloalkylcarbonyl, cycloalkylsulfonyl,heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl,heterocyclealkylsulfonyl, heterocyclearylcarbonyl,heterocyclearylsulfonyl, heterocyclecarbonyl,heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl,heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl,heterocycleoxyarylsulfonyl, heterocyclesulfonyl, andheterocyclethioalkylcarbonyl; R₇ is hydrogen; and R₈ is selected fromthe group consisting of alkylcarbonyl, cycloalkylcarbonyl, aryl,heterocycle, heterocyclecarbonylaryl and heterocyclecarbonylheterocycle.3. A compound according to claim 1 wherein R₁ is NR₃R₄; R₃ and R₄ areindependently selected from the group consisting of hydrogen,alkenyloxycarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl,aminocarbonyl, aminosulfonyl, arylalkenylsulfonyl, arylcarbonyl,arylsulfonyl, cycloalkylcarbonyl, heterocyclecarbonyl,heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl,heterocycleoxyarylsulfonyl, heterocyclesulfonyl andheterocyclethioalkylcarbonyl; R₇ is hydrogen; and R₈ is selected fromthe group consisting of alkylcarbonyl, cycloalkylcarbonyl, aryl,heterocycle, heterocyclecarbonylaryl and heterocyclecarbonylheterocycle.4. A compound according to claim 1 wherein Z is CH₂; R₁ is NR₃R₄; R₃ andR₄ are independently selected from the group consisting of hydrogen,alkoxycarbonyl and alkyl; R₇ is hydrogen; R₈ is selected from the groupconsisting of acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl,4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl,2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen.
 5. A compound according to claim 4selected from the group consisting of tert-butyl1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}-3-pyrrolidinylcarbamate;N,N-dimethyl-N-[(3S)-1-(3-{[4′-(1-pyrrolidinylcarbonyl)[1,1′-biphenyl]-4-yl]oxy}propyl)pyrrolidinyl]amine;andN,N-dimethyl-N-[(3S)-1-(3-{4-[4-(1-pyrrolidinylcarbonyl)-1-piperazinyl]phenoxy}propyl)pyrrolidinyl]amine.6. A compound according to claim 1 wherein Z is a covalent bond; R₁ isNR₃R₄; R₃ and R₄ are independently selected from the group consisting ofhydrogen, alkoxycarbonyl and alkyl; R₇ is hydrogen; R₈ is selected fromthe group consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen.
 7. A compound according to claim 6that is tert-butyl(3S)-1-{2-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]ethyl}pyrrolidinylcarbamate.8. A compound according to claim 1 of formula II

or a pharmaceutically acceptable salt thereof wherein R₁₀ is selectedfrom the group consisting of alkenyl, alkyl, alkynyl, amino, aryl,arylalkenyl, arylalkyl, arylaryl, arylheterocycle, aryloxyaryl,cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl,heterocyclearyl, heterocycleheterocycle and heterocycleoxyaryl.
 9. Acompound according to claim 8 wherein R₃ is selected from the groupconsisting of hydrogen and alkyl; R₈ is selected from the groupconsisting of alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle,heterocyclecarbonylaryl and heterocyclecarbonylheterocycle; R₁₀ isselected from the group consisting of alkyl, amino, aryl, arylalkenyl,heterocycle, heterocycleheterocycle and heterocycleoxyaryl.
 10. Acompound according to claim 8 wherein Z is CH₂; R₃ is selected from thegroup consisting of hydrogen and alkyl; R₈ is selected from the groupconsisting of acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl,4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl,2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₀ is selected from the groupconsisting of alkyl and amino.
 11. A compound according to claim 10selected from the group consisting ofN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-propanesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-propanesulfonamide;N-[(3R)-1-[3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl]pyrrolidinyl]-N,N′,N′-trimethyl-sulfamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-propanesulfonamide;andN′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N-dimethylsulfamide.12. A compound according to claim 8 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen and alkyl; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₀ is aryl wherein said aryl isphenyl optionally substituted with 1 or 2 substitutuents selected fromthe group consisting of alkoxy, alkyl, alkylsufonyl, amino, cyano,haloalkoxy, haloalkyl, halogen.
 13. A compound according to claim 12selected from the group consisting ofN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-cyanobenzenesulfonamide;4-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;4-bromo-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;4-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-10-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;N-(4-{[((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methoxybenzenesulfonamide;4-tert-butyl-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2,5-dimethoxybenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-methylbenzenesulfonamide;3-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-ethylbenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-isopropylbenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-fluorobenzenesulfonamide;2-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl-4-yl)oxy]propyl}pyrrolidinyl]benzenesulfonamide;3-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;3,5-dichloro-N-((3R)-1-{3-[(4′-cyano-[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;4-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;3-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,5-bis(trifluoromethyl)benzenesulfonamide;4-butoxy-N-((3R)1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,4-dimethoxybenzenesulfonamide;3-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-(trifluoromethoxy)benzenesulfonamide;2-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-methylbenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-fluorobenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethoxy)benzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2,4-difluorobenzenesulfonamide;N-(2-chloro-4-{[((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;3,4-dichloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;4-bromo-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;4-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methoxybenzenesulfonamide;4-tert-butyl-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-(trifluoromethyl)benzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2,5-dimethoxybenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-methylbenzenesulfonamide;3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-ethylbenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)4-isopropylbenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-fluorobenzenesulfonamide;2-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;3-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-3-fluorobenzenesulfonamide;N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-(trifluoromethoxy)benzenesulfonamide;N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2,4-difluorobenzenesulfonamide;N-{4-[({(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}amino)sulfonyl]-2-chlorophenyl}acetamide;N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-3,4-dichlorobenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3,5-bis(trifluoromethyl)benzenesulfonamide;4-butoxy-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3,4-dimethoxybenzenesulfonamide;3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-(trifluoromethoxy)benzenesulfonamide;2-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-methylbenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-fluorobenzenesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-(trifluoromethoxy)benzenesulfonamide;N-(2-chloro-4-{[((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;3,4-dichloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;4-methoxy-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;4-isopropyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;4-cyano-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;3-cyano-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;3,4-dimethoxy-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;N-(2-chloro-4-{[((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-fluoro-N-methylbenzenesulfonamide;4-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylbenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-isopropyl-N-methylbenzenesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-4-(methylsulfonyl)benzenesulfonamide;andN-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(methylsulfonyl)benzenesulfonamide.14. A compound according to claim 8 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen and alkyl; R₉ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogewn; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₀ is arylalkenyl wherein thearyl portion of said arylalkenyl is phenyl.
 15. A compound according toclaim 14 selected from the group consisting ofN-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-phenylethenesulfonamide;andN-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-phenylethenesulfonamide.16. A compound according to claim 8 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen and alkyl; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₀ is heterocycle wherein saidheterocycle is selected from the group consisting of benzothienyl,imidazolyl, isoquinolinyl, pyridinyl, pyrrolyl, quinolinyl, thiazolyland thienyl, wherein said benzothienyl, imidazolyl, isoquinolinyl,pyridinyl, pyrrolyl, quinolinyl, thiazolyl and thienyl are optionallysubstituted with 1 or 2 substitutuents selected from the groupconsisting of alkoxy, alkyl, amino, haloalkyl, and halogen.
 17. Acompound according to claim 16 selected from the group consisting ofN-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-1-methyl-1H-imidazole-4-sulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-thiophenesulfonamide;5-chloro-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-methyl-1-benzothiophene-2-sulfonamide;N-(5-{[((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}-4-methyl-1,3-thiazol-2-yl)acetamide;N-((3R)-1-{3-[(4′-cyano[1,1-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-8-quinolinesulfonamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-7-isoquinolinesulfonamide;N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-isoquinolinesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-1-methyl-1H-imidazole-4-sulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-thiophenesulfonamide;5-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-methyl-1-benzothiophene-2-sulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propylpyrrolidinyl)-8-quinolinesulfonamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-8-isoquinolinesulfonamide;and1-methyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)-1H-imidazole-4-sulfonamide.18. A compound according to claim 8 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen and alkyl; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₀ is heterocycleheterocyclewherein said heterocycleheterocycle is(3-chloro-5-(trifluoromethyl)-2-pyridinyl)-1H-pyrrol-2-yl.
 19. Acompound according to claim 18 that isN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1H-pyrrole-2-sulfonamide.20. A compound according to claim 8 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen and alkyl; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halgoen; and R₁₀ is heterocycleoxyarylwherein said heterocycleoxyaryl is(3-chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenyl).
 21. A compoundaccording to claim 20 that isN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}benzenesulfonamide.22. A compound according to claim 1 of formula III

or a pharmaceutically acceptable salt thereof wherein R₁₁ is selectedfrom the group consisting of hydrogen, alkenyl, alkenyloxy, alkoxy,alkyl, alkynyl, alkynyloxy, amino, aryl, arylalkenyl, arylalkyl,arylaryl, arylheterocycle, aryloxyaryl, cycloalkyl, cycloalkylalkyl,heterocycle, heterocyclealkyl, heterocyclearyl, heterocycleheterocycle,heterocycleoxyalkyl, heterocycleoxyaryl and heterocyclethioalkyl.
 23. Acompound according to claim 22 wherein R₃ is selected from the groupconsisting of hydrogen, alkyl, alkylcarbonyl, aminocarbonyl,arylcarbonyl, and heterocyclecarbonyl; R₈ is selected from the groupconsisting of alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle,heterocyclecarbonylaryl and heterocyclecarbonylheterocycle; and R₁₁ isselected from the group consisting of alkenyloxy, alkoxy, alkyl, amino,aryl, cycloalkyl, heterocycle, heterocycleheterocycle andheterocyclethioalkyl.
 24. A compound according to claim 22 wherein Z isCH₂; R₃ is selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, and aminocarbonyl; R₈ is selected from the groupconsisting of acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl,4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl,2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₁ is selected from the groupconsisting of alkenyloxy, alkoxy, alkyl, amino, and cycloalkyl.
 25. Acompound according to claim 24 selected from the group consisting ofN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}cyclopropanecarboxamide;tert-butyl(3R)-1-{2-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]ethyl}pyrrolidinylcarbamate;tert-butyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylacetamide;N-((3R)-1-3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,3,3-trimethylbutanamide;methyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;tert-pentyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N′,N′-trimethylurea;N′-tert-butyl-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylurea;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)acetamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,3-dimethylbutanamide;allyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;methyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;tert-pentyl(3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N-dimethylurea;N-(tert-butyl)-N′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)urea;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(3,3-dimethylbutanoyl)-3,3-dimethylbutanamide;andN′-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N′-(dimethylaminocarbonyl)-N,N-dimethylurea.26. A compound according to claim 22 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen, alkyl, and arylcarbonyl whereinthe aryl portion of said arylcarbonyl is phenyl optionally substitutedwith 1 substituent selected from the group consisting of cyano andhalogen; R₈ is selected from the group consisting of acetyl, propionyl,cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₁ is aryl wherein said aryl isphenyl optionally substituted with 1 substituent selected from the groupconsisting of cyano and halogen.
 27. A compound according to claim 26selected from the group consisting ofN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-cyanobenzamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluoro-N-methylbenzamide;4-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylbenzamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluoro-N-(4-fluorobenzoyl)benzamide;N-((3R)-1-{3-[(4′-cyano[1,1-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzamide;and4-cyano-N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzamide.28. A compound according to claim 22 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen, alkyl, and heterocyclecarbonylwherein the heterocycle portion of said heterocyclecarbonyl is selectedfrom the group consisting of 4-morpholinyl and 1-pyrrolidinyl; R₉ isselected from the group consisting of acetyl, propionyl,cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₁ is heterocycle wherein saidheterocycle is selected from the group consisting of furyl,4-morpholinyl, pyridinyl, and pyrrolidinyl.
 29. A compound according toclaim 28 selected from the group consisting ofN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}nicotinamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-1-pyrrolidinecarboxamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-4-morpholinecarboxamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylnicotinamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-2-furamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-1-pyrrolidinecarboxamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-morpholinecarboxamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)nicotinamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-furamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(1-pyrrolidinylcarbonyl)-1-pyrrolidinecarboxamide;andN-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(4-morpholinylcarbonyl)-4-morpholinecarboxamide.30. A compound according to claim 22 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen and alkyl; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₁ is heterocycleheterocyclewherein said heterocycleheterocycle is 2-(3-pyridinyl)-1,3-thiazol-4-yl.31. A compound according to claim 30 selected from the group consistingofN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;N-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;andN-((3R)-1-{3-[(4′-cyano[1,1′-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide.32. A compound according to claim 22 wherein Z is CH₂; R₃ is selectedfrom the group consisting of hydrogen and alkyl; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen; and R₁₁ is heterocyclethioalkylwherein said heterocyclethioalkyl is[(4-methyl-2-pyrimidinyl)sulfanyl]methyl.
 33. A compound according toclaim 32 that isN-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-[(4-methyl-2-pyrimidinyl)sulfanyl]acetamide.34. A compound according to claim 1 of formula IV

or a pharmaceutically acceptable salt thereof wherein R₃ and R₄ areindependently selected from the group consisting of hydrogen, alkenyl,alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle andheterocyclealkyl.
 35. A compound according to claim 34 wherein R₃ and R₄are independently selected from the group consisting of hydrogen andalkyl; R₈ is selected from the group consisting of alkylcarbonyl,cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl andheterocyclecarbonylheterocycle.
 36. A compound according to claim 34wherein Z is CH₂; R₃ and R₄ are independently selected from the groupconsisting of hydrogen and alkyl; R₈ is selected from the groupconsisting of acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl,4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl,2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; and R₉ is hydrogen; andR_(A), R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen.
 37. A compound according to claim 36selected from the group consisting of1-(4-{3-[(3R)-3-aminopyrrolidinyl]propoxy}phenyl)-1-propanone;4′-{3-[(3R)-3-aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;4′-{3-[(3R)-3-(dimethylamino)pyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;4′-{3-[(3R)-3-(methylamino)pyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1′-biphenyl-4-carbonitrile;4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2-methyl-1,1′-biphenyl-4-carbonitrile;and4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-fluoro-1,1′-biphenyl-4-carbonitrile.38. A compound according to claim 34 wherein Z is CH₂; R₃ and R₄ areindependently alkyl; R₈ is selected from the group consisting of acetyl,propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl,4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl,4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; and R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen, alkoxy, alkyl and halogen.
 39. A compoundaccording to claim 34 wherein Z is CH₂; R₃ and R₄ are independentlyalkyl; R₈ is 4-cyanophenyl; R₉, R_(B), R_(C) and R_(D) are hydrogen; andR_(A) is selected from the group consisting of alkoxy, alkyl andhalogen.
 40. A compound according to claim 39 selected from the groupconsisting of4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-fluoro-1,1′-biphenyl-4-carbonitrile;4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-methyl-1,1′-biphenyl-4-carbonitrile;4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-iodo-1,1′-biphenyl-4-carbonitrile;3′-chloro-4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-1,1′-biphenyl-4-carbonitrile;and4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-methoxy-1,1′-biphenyl-4-carbonitrile.41. A compound according to claim 34 wherein Z is CH₂; R₃ and R₄ areindependently alkyl; R₈ is 4-cyanophenyl; R₉, R_(A), R_(C) and R_(D) arehydrogen; and R_(B) is alkyl.
 42. A compound according to claim 41 thatis4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2′-methyl-1,1′-biphenyl-4-carbonitrile.43. A compound according to claim 34 wherein Z is CH₂; R₃ and R₄ areindependently alkyl; R₈ is 4-cyanophenyl; R₉, R_(B) and R_(C) arehydrogen; and R_(A) and R_(D) are independently halogen.
 44. A compoundaccording to claim 41 selected from the group consisting of4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′,5′-difluoro-1,1′-biphenyl-4-carbonitrile;and3′-chloro-4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-5′-fluoro-1,1′-biphenyl-4-carbonitrile.45. A compound according to claim 1 of formula V

or a pharmaceutically acceptable salt thereof.
 46. A compound accordingto claim 45 wherein R₈ is selected from the group consisting ofalkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle,heterocyclecarbonylaryl and heterocyclecarbonylheterocycle.
 47. Acompound according to claim 45 wherein Z is CH₂; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; R₉ is hydrogen; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen.
 48. A compound according to claim 47selected from the group consisting of cyclopropyl{4-[3-(3-hydroxy-1-pyrrolidinyl)propoxy]phenyl}methanone;cyclopropyl(4-{3-[(3R)-3-hydroxypyrrolidinyl]propoxy}phenyl)methanone;4′-{3-[(3R)-3-hydroxypyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;4′-{3-[(3S)-3-hydroxypyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile;4′-[3-(3-hydroxy-3-methyl-1-pyrrolidinyl)propoxy][1,1′-biphenyl]-4-carbonitrile;4′-[3-(3-hydroxy-3-isopropyl-1-pyrrolidinyl)propoxy][1,1′-biphenyl]-4-carbonitrile;and4′-{3-[(3R)-3-hydroxy-3-methylpyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile.49. A compound according to claim 1 of formula VI

or a pharmaceutically acceptable salt thereof.
 50. A compound accordingto claim 49 wherein R₈ is selected from the group consisting ofalkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle,heterocyclecarbonylaryl and heterocyclecarbonylheterocycle.
 51. Acompound according to claim 49 wherein Z is CH₂; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; and R₉ is hydrogen; andR_(A), R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen.
 52. A compound according to claim 51that is 4′-[3-(3-oxo-1-pyrrolidinyl)propoxy][1,1′-biphenyl]-4-carbonitrile.
 53. A compound according to claim 1 of formula VII

or a pharmaceutically acceptable salt thereof.
 54. A compound accordingto claim 53 wherein R₈ is selected from the group consisting ofalkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle,heterocyclecarbonylaryl and heterocyclecarbonylheterocycle.
 55. Acompound according to claim 53 wherein Z is CH₂; R₈ is selected from thegroup consisting of acetyl, propionyl, cyclopropylcarbonyl,4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl,4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl,4-(1-pyrrolidinylcarbonyl)-1-piperazinyl,4-(1-piperidinylcarbonyl)phenyl,4-(1-piperidinylcarbonyl)-1-piperazinyl,4-(4-morpholinylcarbonyl)phenyl,4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl,4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyland 4-(1-piperazinylcarbonyl)-1-piperazinyl; and R₉ is hydrogon; R_(A),R_(B), R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen and halogen.
 56. A compound according to claim 55selected from the group consisting of(5R)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedione;(5S)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedione;and(5R)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-isopropyl-2,4-imidazolidinedione.57. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in combination with a pharmaceuticallyacceptable carrier.
 58. A method for modulating the effects of thehistamine-3 receptor in a mammal comprising administering atherapeutically effective amount of a compound of claim
 1. 59. A methodof treating a disorder wherein the disorder is ameliorated by modulatingthe the histamine-3 receptor in a mammal in need of such treatmentcomprising administering a therapeutically effective amount of acompound of claim
 1. 60. The method of claim 59 wherein the disorder isselected from the group consisting of acute myocardial infarction,asthma, bipolar disorder, cognitive enhancement, cognitive deficits inpsychiatric disorders, cutaneous carcinoma, drug abuse, depression,gastrointestinal disorders, inflammation, jet lag, medullary thyroidcarcinoma, melanoma, Meniere's disease, migraine, mood and attentionalteration, motion sickness, neurogenic inflammation, obsessivecompulsive disorder, pain, Parkinson's disease, schizophrenia, seizures,septic shock, Tourette's syndrome, vertigo, and wakefulness.
 61. Themethod according to claim 59 wherein the disorder is Alzheimer'sdisease.
 62. The method according to claim 59 wherein the disorder isattention-deficit hyperactivity disorder.
 63. The method according toclaim 59 wherein the disorder is epilepsy.
 64. The method according toclaim 59 wherein the disorder is narcolepsy.
 65. The method according toclaim 59 wherein the disorder is obesity.
 66. The method of claim 59wherein the disorder is selected from the group consisting of mildcognitive impairment, deficits of memory, deficits of learning anddementia.